Compounds containing oxazolidinone moiety and uses thereof

ABSTRACT

A compound and method for producing an enantiomerically enriched epoxide from an olefin using a chiral ketone and an oxidizing agent is disclosed. In particular, the compound is of the formula: I wherein R 1 , R 2 , R 3  and R 4  are those defined herein.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

[0001] The U.S. Government has a paid-up license in this invention andthe right in limited circumstances to require the patent owner tolicense others on reasonable terms as provided for by the terms of GrantNo. GM-59705 awarded by the National Institutes of Health.

FILED OF THE INVENTION

[0002] The present invention is directed to a chiral ketone and methodsfor using the same. In particular, the present invention is directed tousing the chiral ketone and an oxidizing agent to epoxidize olefins.

BACKGROUND OF THE INVENTION

[0003] Epoxides are very important chiral building blocks for thesynthesis of enantiomerically pure complex molecules. Asymmetricepoxidation of olefins presents a powerful strategy for the synthesis ofenantiomerically enriched epoxides.

[0004] Among many epoxidation methods, chiral dioxiranes generated illsitu from an oxidizing agent and a chiral ketone have appeared to bepromising reagents for asymmetric epoxidations. Since the firstasymmetric epoxidation of olefins with dioxirane were reported in 1984,significant progress has been made in the area. A variety of cyclicchiral ketones have been used as catalysts to achieve enantioselectivityfor the epoxidation of olefins.

[0005] However, there is a still need for an inexpensive, readilyavailable, and general asymmetric epoxidation catalyst which canepoxidize a variety of olefins, in particular for cis and terminalolefins, with high enantioselectivity.

SUMMARY OF THE INVENTION

[0006] One aspect of the present invention provides a compound of theformula:

[0007] where one of R¹ and R² is —OR^(a) and the other is-alkylene-OR^(b), where each of R^(a) and R^(b) is independently anon-ring forming hydroxy protecting group, or R¹ and R² together withthe carbon atoms to which they are attached to form an optionallysubstituted heterocyclyl; and each of R³ and R⁴ is independentlyhydrogen or —OR^(c), where R^(c) is a non-ring forming hydroxyprotecting group, or R³ and R⁴ together with the carbon atoms to whichthey are attached to form an optionally substituted heterocyclyl,provided at least one of R¹ and R² together with the carbon atoms towhich they are attached to or R³ and R⁴ together with the carbon atomsto which they are attached to form an optionally substituted nitrogenatom containing heterocyclyl.

[0008] In one embodiment, Compound of Formula I is used to produce anasymmetric epoxide from an olefin in the presence of an oxidizing agent.

[0009] Another aspect of the present invention provides, a method forproducing a spiro-bicyclic compound of the formula:

[0010] wherein each of R³ and R⁴is independently hydrogen or —OR^(c),where R^(c) is a non-ring forming hydroxy protecting group, or R³ and R⁴together with the carbon atoms to which they are attached to form anoptionally substituted heterocyclyl; and R⁷ is selected from the groupconsisting of hydrogen, alkyl, aryl, —(R⁸)_(n)—C(═O)—R⁹, and othernitrogen protecting group, where n is 0 or 1, R⁸ is alkylene, and R⁹ ishydroxy, alkyl, alkoxy, —NR^(a)R^(b) (where R^(a) and R^(b) isindependently hydrogen or alkyl), aryl and aryloxy; said methodcomprising:

[0011] (a) contacting a carbohydrate with an amine under conditionsufficient to produce an amino tetrahydroxy carbohydrate;

[0012] (b) protecting two hydroxy groups by contacting the aminotetrahydroxy carbohydrate with a hydroxy protecting group underconditions sufficient to produce a dihydroxy-protected amino dihydroxycarbohydrate;

[0013] (c) forming a heterocyclic moiety by contacting thedihydroxy-protected amino dihydroxy carbohydrate with an activatedcarbonate under conditions sufficient to produce a hydroxyspiro-bicyclic compound; and

[0014] (d) oxidizing the hydroxy group contacting the hydroxyspiro-bicyclic compound with an oxidizing agent under conditionssufficient to produce the spiro-bicyclic compound of Formula IA.

[0015] Preferably, the spiro-bicyclic compound is enantiomericallyenriched chiral compound. More preferably, the enantiomerically enrichedspiro-bicyclic compound is of the formula:

[0016] or stereoisomers thereof, where R³, R⁴ and R⁷ are those definedherein. And most preferably, the enantiomerically enrichedspiro-bicyclic compound is of the formula:

[0017] or a stereoisomer thereof, wherein R⁷ is that defined herein; andeach of R¹⁰ and R¹¹ is independently selected from the group consistingof hydrogen, alkyl, aralkyl and aryl.

[0018] In one particular embodiment, the carbohydrate, e.g., startingmaterial, is glucose, preferably (D)- or (L)-glucose.

[0019] In one embodiment, the amine is diaralkyl amine. In such anembodiment, the method can further include the steps of removing aralkylgroups from the amino nitrogen by contacting the dihydroxy-protectedamino dihydroxy carbohydrate with hydrogen in the presence of ahydrogenation catalyst under conditions sufficient to produce adihydroxy-protected free-amino carbohydrate prior to said heterocyclicmoiety forming step (c).

[0020] Yet another aspect of the present invention provides a method forproducing a fused-bicyclic compound of the formula:

[0021] wherein R¹³ and R¹⁴ are hydroxy protecting groups or R¹³ and R¹⁴together with the carbon atoms to which they are attached to form anoptionally substituted heterocyclyl; and R¹⁵ is same as R⁷ definedherein;

[0022] said method comprising

[0023] (a) contacting a trihydroxy-protected olefin compound of theformula:

[0024] where

[0025] R¹³ and R¹⁴ are hydroxy protecting groups or R¹³ and R¹⁴ togetherwith the carbon atoms to which they are attached to form an optionallysubstituted heterocyclyl; and

[0026] R¹² is a hydroxy protecting group, with a hydroxy aminating agentunder conditions sufficient to produce an amino hydroxy compound of theformula:

[0027] where

[0028] R¹², R¹³, R¹⁴ and R¹⁵ are those defined herein;

[0029] (b) forming a heterocyclic moiety by contacting the amino hydroxycompound with an activated carbonate under conditions sufficient toproduce a fused bicyclic compound of the formula:

[0030] where

[0031] R¹², R¹³, R¹⁴ and R¹⁵ are those defined herein;

[0032] (c) selectively removing the R¹² hydroxy protecting group bycontacting the fused bicyclic compound with a hydroxy protecting groupremoving agent under conditions sufficient to produce a monohydroxyfused bicyclic compound of the formula:

[0033] where

[0034] R¹³, R¹⁴ and R¹⁵ are those defined above;

[0035] and

[0036] (d) oxidizing the free hydroxy group by contacting themonohydroxy fused bicyclic compound with an oxidizing agent underconditions sufficient to produce the fused-bicyclic compound of FormulaV.

[0037] In this embodiment, R¹⁵ can be converted to a desired substituentprior to or after the heterocyclyl moiety forming step (b) or after theoxidizing step (d). For example, when R¹⁵ of compound of Formula VII istosyl, the method can further comprise converting R¹⁵ of compound ofFormula VII to hydrogen, alkyl, aryl, —(R⁸)_(n)—C(═O)—R⁹, or othernitrogen protecting group, prior to said heterocyclic moiety formingstep (b), said converting step comprising:

[0038] (i) removing the tosyl group of compound of Formula VII bycontacting the compound of Formula VII with a tosyl removing agent underconditions sufficient to provide a compound of Formula VII comprising afree amine group, where R¹⁵ is hydrogen; and

[0039] (ii) optionally substituting the free amine group by contactingthe compound of Formula VII comprising a free amine group with acompound of the formula R⁷—X under conditions sufficient to produce acompound of Formula VII,

[0040] wherein

[0041] R⁷ and R¹⁵ are identical and is selected from the groupconsisting of alkyl, aryl, —R⁸)_(n)—C(═O)—R⁹, or other nitrogenprotecting group, where n, R⁸ and R⁹ are those defined herein; and

[0042] X is a leaving group.

[0043] Alternatively, when R¹⁵ of compound of Formula V is tosyl, themethod can further comprise converting R¹⁵ of compound of Formula V tohydrogen, alkyl, aryl, —(R⁸)_(n—C(═O)—R) ⁹, or other nitrogen protectinggroup, after said oxidizing step (d), said converting step comprising:

[0044] (i) removing the tosyl group of compound of Formula V bycontacting the compound of Formula V with a tosyl removing agent underconditions sufficient to provide a compound of Formula V comprising afree amine group, where R¹⁵ is hydrogen; and

[0045] (ii) optionally substituting the free amine group by contactingthe compound of Formula V comprising a free amine group with a compoundof the formula R⁷—X under conditions sufficient to produce a compound ofFormula V, wherein

[0046] R⁷ and R¹⁵ are identical and is selected from the groupconsisting of alkyl, aryl, —(R⁸)_(n)—C(═O)—R⁹, or other nitrogenprotecting group, where n, R⁸ and R⁹ are those defined herein; and

[0047] X is a leaving group.

[0048] Preferably, the trihydroxy-protected olefin compound is producedfrom a carbohydrate. In one embodiment of the present invention, thetrihydroxy-protected olefin compound producing step comprises:

[0049] (i) selectively protecting hydroxy groups of the carbohydratewith at least two different hydroxy protecting groups by contacting thecarbohydrate with a first hydroxy protecting agent under conditionssufficient to produce a first carbohydrate comprising a first hydroxyprotecting group and contacting the first carbohydrate with a secondhydroxy protecting agent under conditions sufficient to produce a secondcarbohydrate comprising a first and a second hydroxy protecting groups,wherein the first and the second hydroxy protecting groups can beselectively removed;

[0050] (ii) removing at least a portion of the first hydroxy protectinggroup by contacting the second carbohydrate with a first hydroxyprotecting group removing agent under conditions sufficient to produce adi-free hydroxy carbohydrate; and

[0051] (iii) forming an olefinic bond by contacting the di-free hydroxycarbohydrate with a dihydroxy eliminating agent under conditionssufficient to produce the trihydroxy-protected olefin compound.

BRIEF DESCRIPTION OF THE DRAWINGS

[0052] FIG. 1 is ORTEP view of X-ray structure of ketones IVa (left) andIVb (right); and

[0053] FIG. 2 is ORTEP view of X-ray structure of ketones IVd (left) andIVe (right).

DETAILED DESCRIPTION OF THE INVENTION

[0054] “Alkyl” refers to a linear saturated monovalent hydrocarbonmoiety of one to ten carbon atoms or a branched saturated monovalenthydrocarbon moiety of three to ten carbon atoms. In addition, the alkylgroup can be substituted with one or more halides, alkoxides, hydroxidesor carbonyl groups. Exemplary alkyl groups include methyl, ethyl,propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl,trifluoromethyl, and the like.

[0055] “Aralkyl” refers to a moiety of the formula —R^(a)R^(b) whereR^(a) is an alkylene group and R^(b) is an aryl group as defined herein.

[0056] “Aryl” refers to a monovalent monocyclic or bicyclic aromatichydrocarbon moiety of 6 to 10 ring atoms which is optionally substitutedwith one or more substituents, preferably one, two, or threesubstituents. Suitable substituents of aryl group include alkyl, halo,nitro, cyano, cycloalkyl, hydroxy, alkoxy, —NR^(a)R^(b) (where R^(a) ishydrogen or alkyl and R^(b) is hydrogen, alkyl or a nitrogen protectinggroup), and the like.

[0057] “Carbohydrate” refers to natural or unnatural hydrocarbon moietycomprising six carbon atoms, a carbonyl carbon (or equivalents thereof,e.g., a carbon atom comprising an acetal or a ketal functionality) and aplurality of free hydroxy groups, preferably three or more free hydroxygroups, and more preferably five free hydroxy groups.

[0058] “Free hydroxy group” refers to a non-protected hydroxy group,i.e., a moiety of the formula —OH.

[0059] “Fused heterocyclyl” refers to a fused moiety consisting of aheterocyclic ring having two carbon atoms in common with the ring towhich it is attached to. The fused moiety is formed when two hydrogenatoms from two different carbon atoms of the ring are replaced with aheterocyclyl group as defined herein.

[0060] “Heteroaralkyl” means a moiety of the formula —R^(a)R^(b) whereR^(a) is an alkylene group and R^(b) is a heteroaryl group as definedherein.

[0061] “Heteroaryl” means a monovalent monocyclic or bicyclic aromaticradical of 5 to 12 ring atoms containing one, two, or three ringheteroatoms selected from N, O, or S, the remaining ring atoms being C.The heteroaryl ring can optionally be substituted independently with oneor more substituents, preferably one or two substituents.

[0062] “Heterocyclyl” refers to a saturated or unsaturated non-aromaticcyclic moiety of 3 to 8 ring atoms in which one or more, preferably atleast two, ring atoms are heteroatoms selected from N, or O, theremaining ring atoms being C, where one or two ring C atoms mayoptionally be substituted with a carbonyl oxygen (i.e., ═O). As such, aheterocyclyl includes acetonides that are formed by protection of1,2-diol or 1,3-diol with an aldehyde or a ketone. The heterocyclyl ringmay be optionally substituted independently with one, two, three, orfour substituents selected from alkyl, haloalkyl, heteroalkyl, halide,hydroxy, alkoxy, amino, monoalkylamino, and dialkylamino. Morespecifically the term heterocyclyl includes, but is not limited to,1,3-dioxolanyl, 2-oxazolidinonyl, and the derivatives thereof.

[0063] “Leaving group” has the meaning conventionally associated with itin synthetic organic chemistry, i.e., an atom or a group capable ofbeing displaced by a nucleophile and includes halides (such as chloride,bromide, and iodide), alkanesulfonyloxy, arenesulfonyloxy,alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy,trifluoromethanesulfonyloxy, aryloxy (e.g., 2,4-dinitrophenoxy),methoxy, N,O-dimethylhydroxylamino, and the like.

[0064] “Monohydroxy carbohydrate” refers to a natural or unnaturalcarbohydrate comprising one free hydroxy group. Similarly, dihydroxycarbohydrate, trihydroxy carbohydrate, and tetrahydroxy carbohydraterefer to natural or unnatural carbohydrate comprising two, three andfour free hydroxy groups, respectively.

[0065] “Nitrogen atom containing heterocyclyl” refers to heterocyclyl asdefined herein where at least one of the ring atom is nitrogen.

[0066] “N-membered heterocyclyl” refers to a heterocyclyl as definedherein which comprises n number of atoms within the heterocyclyl ringsystem.

[0067] “Non-ring forming hydroxy protecting group” refers to a hydroxyprotecting group that does not form a ring system when used to protect1,2-diol or 1,3-diol group.

[0068] “Protecting group” refers to a grouping of atoms that whenattached to a reactive group in a molecule masks, reduces or preventsthat reactivity. Examples of protecting groups can be found inProtective Groups in Organic Synthesis, 3rd edition, T. W. Greene and P.G. M. Wuts, John Wiley & Sons, New York, 1999, and Harrison and Harrisonet al., Compendium of Synthetic Organic Methods, Vols. 1-8 (John Wileyand Sons, 1971-1996), all of which are incorporated herein by referencein their entirety. Representative amide protecting groups include,formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ),tert-butoxycarbonyl (Boc), trimethyl silyl (TMS),2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted tritylgroups, carbamates, and the like.

[0069] “Spiro-heterocyclyl” refers to a spiro moiety consisting of aheterocyclic ring having only one carbon atom in common with the ring towhich it is attached to. The spiro moiety is formed when two hydrogenatoms from the same carbon atom of the ring are replaced with aheterocyclyl group as defined herein.

[0070] As used herein, the terms “treating”, “contacting” or “reacting”,when referring to a chemical reaction, are used interchangeably andrefer to adding or mixing two or more reagents under appropriateconditions to produce the indicated and/or the desired product. Itshould be appreciated that the reaction which produces the indicatedand/or the desired product may not necessarily result directly from thecombination of two reagents which were initially added, i.e., there maybe one or more intermediates which are produced in the mixture whichultimately leads to the formation of the indicated and/or the desiredproduct.

[0071] One aspect of the present invention provides a compound of theformula:

[0072] and methods for producing and using the same, where one of R¹ andR² is —OR^(a) and the other is -alkylene-OR^(b), where each of R^(a) andR^(b) is independently a non-ring forming hydroxy protecting group, orR¹ and R² together with the carbon atoms to which they are attached toform an optionally substituted heterocyclyl; and each of R³ and R⁴ isindependently hydrogen or —OR^(c), where R^(c) is a non-ring forminghydroxy protecting group, or R³ and R⁴ together with the carbon atoms towhich they are attached to form an optionally substituted heterocyclyl,provided at least one of R¹ and R² together with the carbon atoms towhich they are attached to or R³ and R⁴ together with the carbon atomsto which they are attached to form an optionally substituted nitrogenatom containing heterocyclyl. Preferably, the relative stereochemistryof R³ and R⁴ is a cis-configuration.

[0073] Preferably, the heterocyclyl moiety is an optionally substituted5-membered heterocyclyl. More preferably, the heterocyclyl is selectedfrom the group consisting of an optionally substituted2-oxazolidinon-5-yl and an optionally substituted 1,3-dioxolan-4-yl.

[0074] In one particular embodiment of the present invention, R¹ and R²together with the carbon atoms to which they are attached to form anoptionally substituted nitrogen atom containing heterocyclyl. Preferablyin this embodiment, the compound of Formula I is of the formula:

[0075] where R³ and R⁴ are those defined above, preferably R³ and R⁴together with the carbon atoms to which they are attached to form anoptionally subsituted heterocycyl; one of X¹ and X2 is O and the otheris NR⁷, preferably X¹ is O and X² is NR⁷, where R⁷ is selected from thegroup consisting of hydrogen, alkyl, aryl, —(R⁸)_(n)—C(═O)—R⁹, and othernitrogen protecting group, where n is 0 or 1, R⁸ is alkylene, preferablymethylene, and R⁹ is hydroxy, alkyl, alkoxy, —NR^(a)R^(b) (where R^(a)and R^(b) is independently hydrogen or alkyl), aryl and aryloxy; andeach of R⁵ and R⁶ is independently selected from the group consisting ofhydrogen, and alkyl, preferably hydrogen. Preferred R⁷ is—(R⁸)_(n)—C(═O)—R⁹, where n=0. More preferably in this embodiment, thecompound of Formula I is of the formula:

[0076] or a stereoisomer thereof, where R⁷ is that defined herein; andeach of R¹⁰ and R¹¹ is independently selected from the group consistingof hydrogen, alkyl, aralkyl and aryl.

[0077] In another embodiment of the present invention, R³ and R⁴together with the carbon atoms to which they are attached to form anoptionally substituted nitrogen atom containing heterocyclyl. Preferablyin this embodiment, the compound of Formula I is of the formula:

[0078] where R¹, R², X¹ and X² are those defined herein. Preferably inthis embodiment, R¹ and R² together with the carbon atoms to which theyare attached to form an optionally substituted heterocyclyl. Morepreferably in this embodiment, the compound of Formula I is of theformula:

[0079] where R⁷, R¹⁰ and R¹¹ are those defined herein.

[0080] Representative Compounds of Formula I include, but are notlimited to, the compounds listed in Table 1 below: TABLE 1Representative Compounds of Formula I.

[0081] As generally shown above, compounds of the present inventionreplace the fused ketal moiety of 1 with an oxazolidinone moiety or thespiro ketal moiety of 1 with an oxazolidinone moiety.

[0082] Synthesis of Compounds of Formula I

[0083] Compounds of Formula I can be synthesized by a variety of methodsand using any appropriate starting material. For example, chiral cyclicketones of Formula I can be prepared from a carbohydrate. Reasons forselecting a carbohydrate as the starting material include: (a)carbohydrates are chiral and readily available; (b) they are highlysubstituted with oxygen groups, which provide good reactivity, as theinductive effect of oxygen activates the ketone catalyst; and (c)carbohydrate-derived ketones have a relatively rigid conformations dueto the anomeric effect, which is desirable for selectivity. In oneparticular embodiment, Compounds of Formula I are synthesized fromglucose or fructose, preferably from (D))- or (L)-glucose or (D)- or(L)-fructose.

[0084] Synthesis of representative compounds of Formula I will now bedescribed in reference to using a carbohydrate or a derivative thereofas the starting material. However, it should be appreciated that oneskilled in the art can readily use other suitable compounds as thestarting material given the teachings provided herein. Two particularembodiments for preparing representative compounds of Formula I areillustrated in Schems 1 and 2. These schemes are provided for the solepurpose of illustrating the practice of the present invention and arenot intended to constitute limitations on the scope thereof.

[0085] Scheme 1 shows one method of producing a compound of Formula IV,where R¹⁰ and R¹¹ are methyl. In this embodiment a carbohydrate, such as(D)-glucose, is converted to an N-glycoside. Amadori rearrangement ofthe N-glycoside in the presence of an acid, followed by protection ofcis-diol and removal of the amino-protecting group then afforded thedihydroxy-protected amino dihydroxy carbohydrate I-1. Typically, theN-glycoside is produced using a di-substituted amine, preferably one inwhich the substituents can be subsequently removed, which allows one toeasily prepare a wide variety of compounds of Formula IV. Alternatively,one can use a mono-substituted amine which provides the desired compounddirectly. Amadori rearrangement converts an N-glycosides of aldoses toN-glycosides of the corresponding ketoses. Reaction conditions forAmadori rearrangement are well known to one skilled in the art andgenerally involve an alcoholic solvent, such as ethanol, propanol andbutanol. Conveniently, synthesis of N-glycoside and Amadorirearrangement can be carried out in one step. While a wide range ofreaction temperature can used for this transformation, e.g., from about20° C. to about 100° C., generally the reaction is carried out under thesolvent refluxing conditions to produce an amino tetrahydroxycarbohydrate. Suitable acids for Amadori rearrangement include, but arenot limited to, carboxylic acids, such as acetic acid; and othernon-nucleophilic acids.

[0086] The hydroxy groups of the amino tetrahydroxy carbohydrate is thenselectively protected as a ketal by using an orthoester, a ketone or analdehyde in the presence of an acid catalyst. Protection of 1,2-diols asa ketal or an acetal are well known to one skilled in the art. See forexample, Protective Groups in Organic Synthesis, 3rd edition, T. W.Greene and P. G. M. Wuts, John Wiley & Sons, New York, 1999, which isincorporated herein by reference in its entirety.

[0087] The amine is deprotected to yield a primary amine moiety. Asdiscussed in detail below, the use of deprotectable amine allowspreparation of a variety of compounds of Formula IIA by simplealkylation of the amine functional group.

[0088] Alternatively, by using a substituted amine, in particular anaryl or an alkyl amine, in the Amadori rearrangement, one can obtain thecompound of Formula IV having a desired amine substituent as illustratedbelow, where R is an alkyl, or preferably an aryl group:

[0089] The dihydroxy-protected amino dihydroxy carbohydrate I-1 is thenreacted with an activated carbonate to produce a spiro-bicyclic compoundof Formula I-2. Typically, the spiro-bicyclic compound forming reactionincludes a non-nucleophilic base such as a tertiary amine, pyridine, abicarbonate or a carbonate. The reaction is conveniently conducted in aninert organic solvent at temperature 20° C. or below, preferably at 0°C. or below.

[0090] Generally the activated carbonate comprises a carbonatederivative comprising two functional groups selected from the groupconsisting of a halide, alkoxide, aryloxide, alkylthio, carboxylate(e.g., R—C(═O)—O—), derivatives thereof, and mixtures thereof. Exemplaryactivated carbonates include phosgene, triphosgene, a haloformate (i.e.,X—C(═O)—OR, where X is a halide and R is alkyl, aryl or aralkyl), andbis-imidazole carbonyl. When the activated carbonate comprises an estermoiety, the reaction typically further requires addition of a relativelystrong base that is non-nucleophilic, including tertiary amine, such astriethyl amine, and tert-butoxide. Typically, the reaction is conductedin an aprotic solvent such as acetonitrile and dichloromethane. Thereaction temperature is generally at about 0° C. or above, preferablyfrom about 0° C. to room temperature.

[0091] The free hydroxy group of a hydroxy spiro-bicyclic compound ofFormula I-2 is then protected by treating with a hydroxy protectinggroup, e.g., silyl chloride, under conditions conventionally known toone skilled in the art. This protection of the free hydroxy group allowsa selective substitution reaction (e.g., alkylation) on the carbamatenitrogen atom, thereby allowing a convergent and a rapid synthesis of avariety of compounds of Formula I. Typically, the substitution reactionis conducted in the presence of a base to neutralize the acid that isoften generated in the reaction. The substitution reaction isconveniently carried out generally at room temperature or above.Alternatively, by using an appropriately substituted amine in Amadorirearrangement, one can avoid a separate alkylation or substitutionreaction of the carbamate nitrogen atom.

[0092] The protected hydroxy group is then removed by contacting thehydroxy protected spiro-bicyclic compound of Formula I-3 with a hydroxyprotecting group removing agent under conditions sufficient to produce ahydroxy spiro-bicyclic compound. Suitable reaction conditions forremoving the corresponding hydroxy protection group are well known toone skilled in the art.

[0093] The hydroxy group is then oxidized to a carbonyl group bycontacting the hydroxy spiro-bicyclic compound with an oxidizing agentto produce a spiro-bicyclic compound of Formula I-4. Any conventionaloxidizing agents are suitable in this reaction. Exemplary oxidizingagents can be found on a variety of lieterature sources includingMarch's Advanced Organic Chemistry, 5^(th) ed., Smith and March, WileyInterscience Publication, New York, 2001, and Comprehensive OrganicTransformations, 2^(nd) ed., Larock, John Wiley & Sons, Inc., New York,1999, which are incorporated herein by reference in their entirety.

[0094] Scheme 2 shows a method of producing a compound of Formula XII,where R¹⁰ and R¹¹ are methyl.

[0095] In this embodiment hydroxy amination of a trihydroxy-protectedolefin, such as compound of Formula II-1, with a hydroxy aminating agentproduces an amino hydroxy compound of Formula II-2. Suitable hydroxyaminating agents include a mixture of chloramine-T trihydrate andK₂OsO₆H₄; and other X—NH—R¹⁶ compounds where X is a leaving group suchas halide and R¹⁶ is a carbonyl group (e.g., —C(═O)—OR¹⁷, where R¹⁷ isalkoxy, alkyl, aryloxy, or aryl). Typically this reaction is conductedin a mixture of an organic solvent and water, such as aqueousacetonitrile. The reaction is generally conducted at room tempertureovernight. However, typically a higher reaction temperature results in ashorter reaction time, whereas a lower reaction temperature results in alonger reaction time.

[0096] The amino hydroxy compound of Formula II-2 is then reacted withan activated carbonate to produce a fused bicyclic compound of FormulaII-3. Typically, the fused bicyclic moiety forming reaction includes anon-nucleophilic base such as a tertiary amine, pyridine, a bicarbonateor a carbonate. The reaction is conveniently conducted in an inertorganic solvent at temperature 20° C. or below, preferably at 0° C. orbelow.

[0097] When the hydroxy amination reaction is conducted using a mixtureof chloramine-T trihydrate and K₂OsO₆H₄, the resulting product containsa protected amino group, i.e., tosylated amino group. This protectinggroup can be removed by treating the fused bicyclic compound of FormulaII-3 with lithium in liquid ammonia resulting in a free amino fusedbicyclic compound of Formula II-4. The nitrogen atom of the carbamatecan then be further functionalized as described above to provide a widevariety of compounds of Formula XII. Alternatively, the nitrogen atom ofthe carbamate can be functionalized after the oxidation of a hydroxygroup as described below.

[0098] Selective removal of the hydroxy protecting group from the freeamino fused bicyclic compound of Formula II-4 then affords a freehydroxy group which can be oxidized using a conventional oxidizing agentto provide a ketone of Formula II-5. If the carbamate nitrogen atom isnot substituted (i.e., comprises a hydrogen), this ketone can besubjected to a substitution reaction as described above in reference toScheme 1 to afford a wide variety of compounds of Formula XII.

[0099] The trihydroxy-protected olefin, such as compound of FormulaII-1, can be readily prepared from a variety of starting materialsincluding carbohydrates, such as (D)- or (L)-fructose, depending on thedesired stereochemistry of the trihydroxy-protected olefin. For example,as shown in Scheme 3, hydroxy groups of (D)-fructose are protected withtwo different protecting groups to afford protected (D)-fructose II-7.Using two different protecting groups allows selective manipulation ofdesired hydroxy groups. Moreover, because of difference in reactivity,even the ketals in compound of Formula II-7 can be selectivelydeprotected using DDQ to afford a dihydroxy compound of Formula II-8.

[0100] The resulting cis-dihydroxy groups in compound of Formula II-8can be eliminated using a dihydroxy eliminating agent to afford compoundof Formula II-9, which comprises a double bond. Suitable dihydroxyeliminating agents are well known to one skilled in the art andincludes, a mixture of triphenyl phosphine, imidazole, zinc and iodine;and other suitable reagents known to one skilled in the art.

[0101] It should be appreciated that while the hydroxy groups in Schemes1, 2 and 3 are protected using a 1,2-diol protecting agent, one caneasily protect these hydroxy groups using a separate non-cyclic ringforming hydroxy protecting agent. Preferably the protecting groups forhydroxy groups are selected from the group consisting of silyl ethers,ethers, acetals, ketals, esters, ortho esters, sulfonates, phosphatesand mixtures thereof. The protecting groups for two or more hydroxygroups of the carbohydrate or its derivative can be interconnected asshown in Schemes 1, 2 and 3 above. For example, an acetonide or anisopropylidene group protecting 4,5-hydroxy groups of fructose can beconsidered to be “two interconnected acetal protecting groups” sincethey protect two hydroxy groups on the carbohydrate, e.g., fructose andglucose.

[0102] It should also be appreciated that the carbohydrate can bemonosaccharide or polysaccharide. Exemplary carbohydrates includeglucose, fructose, maltose, lactose, mannose, sorbose, ribose, xylose,rhamnose, galactose, talose, arabinose, gulose, sucrose, cellobiose,cellulose, maltonic acid, heparin, chondroitin sulfate, amylose andamylopectin. Preferably, the carbohydrate is selected from the groupconsisting of fructose, sorbose arabinose, mannose and glucose. Morepreferably, the carbohydrate is selected from the group consisting ofD)-glucose, (L)-glucose, (D)-fructose and (L)-fructose.

[0103] The oxidation of a hydroxy group of a carbohydrate to form acarbonyl group is well known to one skilled in the art. For example,pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Swernoxidation condition or other oxidizing conditions can be used to oxidizea hydroxy group of a carbohydrate or its derivative to a ketone compoundof the present invention. Such oxidizing reagents are well known to oneskilled in the art.

[0104] Utility

[0105] Epoxides are used in many industrial processes as chiral buildingblocks for the synthesis of enantiomerically pure complex molecules suchas polymers, surfactants, pesticides, insecticides, insect hormones,insect repellants, pheromones, food flavoring, and drugs. Thestereochemistry of a molecule is important in many of the properties ofthe molecule. For example, it is well known that physiologicalproperties of drugs having one or more chiral centers, i.e.,stereochemical centers, depend on the stereochemistry of a drug's chiralcenter. In addition, properties of a polymer containing a chiralmonomeric unit depend on the enantiomeric purity of the monomer. Thus,it is advantageous to be able to control the stereochemistry of achemical reaction. Since an epoxide serve as an intermediate or astarting material for many chemical compounds, it is especiallydesirable to be able to control the stereochemistry of the epoxideformation.

[0106] Compound of the present invention are useful in asymmetricallyepoxidizing olefins. A chiral center (i.e., stereochemical center, orstereogenic center) is, of course, an atom to which four differentgroups are attached; however, the ultimate criterion of a chiral centeris nonsuperimposability on the mirror image. Facially selective,stereoselective, enantioselective or asymmetric synthetic reactions arethose in which one of a set of stereoisomers is formed exclusively orpredominantly.

[0107] Preferably, one stereoisomer of the epoxide is produced in atleast about 50 percent excess over the other stereoisomer, morepreferably in at least about 80 percent excess, still more preferably inat least about 90 percent excess, and most preferably in at least about95 percent excess. As used in this invention, an “olefin” refers to acompound having an alkene functionality, i.e., a double bond between twocarbon atoms. An olefin can have more than one double bond. If more thanone double bond is present on the olefin, the double bonds can beconjugated or non-conjugated. The olefin can be monosubstituted,di-substituted, tri-substituted or fully substituted. By substituted, itis meant that the olefinic carbon atom is attached to an atom other thanhydrogen atom. For example, the olefinic carbon can be substituted witha halogen atom, silicon atom, another carbon atom, oxygen atom, sulfuratom and/or a metal atom such as tin. Preferably, the olefin is terminalor cis olefin. The di-substituted olefin can be geminal, cis-, ortrans-substituted olefin. Generally for olefins having at least threesubstituent groups, trans-olefin designation refers to the transrelationship between the larger substituents attached to the twodifferent olefinic carbon atoms, whereas cis designation refers to thecis relation between the larger substituents. In addition to cis- andtrans-notation an “E” or “Z” notation can used to denote the relativepriority of the substituent groups. E- and Z-notations denoting thestereoisomers of alkenes are well known to one of ordinary skill in theart.

[0108] Without being bound by a theory, it is believed that contactingan oxidizing agent with a ketone produces a dioxirane. Although somedioxiranes may be isolated under certain conditions, in general they aregenerated and used in situ by contacting (i.e., reacting) a ketone withan oxidizing agent. It is generally believed that it is this dioxiranewhich is generated in situ that is responsible for the formation of anepoxide from the olefin. Moreover, dioxiranes generated in situ fromchiral ketones have been shown to be remarkably promising oxidationreagents for the asymmetric epoxidation of olefins. As disclosed incommonly assigned PCT Patent Application No. PCT/US97/18310, filed onOct. 8, 1997, which is incorporated herein by reference in its entirety,present inventors have found that a carbohydrate (e.g., fructose orglucose) derived ketones are particularly effective epoxidationcatalysts, in that it gives high enantiomeric excess (i.e., ee's) for avariety of olefins including trans- and trisubstituted olefins (eq. 1).

[0109] The present inventors have found that the Compounds of Formula Iare also useful in epoxidizing olefins. In particular, Compounds ofFormula I are particularly useful in epoxidizing cis-, preferablydi-substituted cis-, and terminal olefins with high enantioselectivity.

[0110] The methods of the present invention regenerate the ketone (i.e.,Compound of Formula I); therefore, the ketone can be used in a catalyticamount. The average number of epoxidation of olefins produced by aketone molecule is known as a catalytic turn-over number, or simply aturn-over number. Preferably the ketones of the present invention have aturn-over number of at least about 3, more preferably at least about 10and most preferably at least about 50. Moreover, since the ketones havesuch a high turn-over number, the amount of the ketones required toepoxidize a given amount of olefin can be less than the stoichiometricamount (i.e., one equivalent) of the olefin. Preferably no more thanabout 0.3 equivalents of the ketone is used to epoxidize olefins, morepreferably no more than about 0.05 equivalents, and most preferably nomore than about 0.01 equivalents.

[0111] As stated above, compounds of Formula I can be used in an amountless than the stoichiometric amount relative to the amount of theolefin. It should be appreciated that in situ generation of dioxiranefrom a ketone generally requires the oxidizing agent to be more reactivetowards the ketone than the olefin to avoid competing oxidation ofolefin by the oxidizing agent. However, when the reactivity of theoxidizing agent towards the olefin is similar or greater than itsreactivity towards the ketone, one can use a large excess amount ofketone relative to the amount of olefin to increase the reaction ratebetween the oxidizing agent and the ketone relative to the reaction ratebetween the oxidizing agent and the olefin. In these cases, preferablythe amount of ketone used is at least about 3 times more than the amountolefin, more preferably at least about 5 times, and most preferably atleast about 10 times.

[0112] Any oxidizing agent capable of providing dioxiranes from acorresponding ketone can be used in the present invention. However, foreconomic reasons a relatively inexpensive oxidizing agents such asorganic peracids, hydrogen peroxide, sodium hypochlorite, potassiumperoxomonosulfate, sodium perborate and hypofluoride (HOF) arepreferred. Preferably, the oxidizing agent is potassiumperoxomonosulfate. Non-organic oxidizing agents (i.e, a compound thatdoes not contain any carbon atom) are particularly preferred as theseoxidizing agents and their reaction products can be easily removed fromthe reaction mixture by a simple aqueous extraction. The amount ofoxidizing agent used in the present invention depends on a variety offactors including the reactivity of the ketone, olefin, and thedecomposition rate of the oxidizing agent. Preferably, the amount of anoxidizing agent used is at least about I times the amount of the ketone,more preferably at least about 9 times, and most preferably at leastabout 100 times. In another embodiment of the present invention, theamount of oxidizing agent used is less than about 10 times the amount ofolefin, more preferably less than about 3 times the amount of olefin,and most preferably about 1-2 times the amount of olefin.

[0113] In some cases, the reaction time affects both the yield of theepoxide as well as the enantiomeric excess of the epoxide product. Thus,while in some cases a longer reaction period provides higher yield ofthe epoxide, the enantiomeric excess begins decrease after certainperiod of time. Therefore, obtaining a maximum yield of the epoxidewhile maintaining a sufficient level of enantiomeric excess requires acompromise between the two diametrically opposed results. Preferably,the reaction time is from about 0.1 h to about 24 h, more preferablyfrom about 0.1 h to about 8 h, and most preferably from about 0.1 h toabout 5 h.

[0114] Depending on the oxidizing agent used and the reactionconditions, in some cases the pH of the reaction mixture is also animportant factor for the epoxidation with dioxiranes generated in situ.In such instances, the pH of the reaction mixture is preferablymaintained at from about pH 5 to about pH 14, more preferably from aboutpH 7 to about pH 12, and most preferably from about pH 8 to about pH 11.The pH of the reaction solution can be conveniently achieved by adding asufficient amount of base (or a buffer solution) to maintain the pH atthe desired level. The base can be added separately, it can be added tothe solution containing the ketone, or it can be added to the solutioncontaining the oxidizing agent. Alternatively, a solid mixture of thebase and oxidizing agent can be added to the reaction mixture.Preferably the base is selected from the group consisting of hydroxides,carbonates, bicarbonates, borates and phosphates. More preferably thebase is selected from the group consisting of potassium carbonate,potassium bicarbonate, lithium carbonate, lithium bicarbonate, sodiumcarbonate, sodium bicarbonate, calcium carbonate, sodium borate, sodiumphosphate, potassium phosphate, lithium hydroxide, sodium hydroxide,potassium hydroxide, magnesium hydroxide and calcium hydroxide. Mostpreferably the base is selected from the group consisting of potassiumcarbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate,sodium hydroxide, sodium borate, sodium phosphate, potassium phosphateand potassium hydroxide. Alternatively, the desire pH of the reactioncan be more easily maintained by using a buffer solution.

[0115] In some cases, the yield of epoxide and/or enantioselectivity ofthe reaction is affected by the solvent system used. Typically, anysuitable organic solvent can be used for the present invention.Exemplary solvents include, nitriles such as acetonitrile andpropionitrile, dimethoxymethane (DMM), dimethoxyethane (DME), etherssuch as tetrahydrofuran (THF) and diethyl ether (Et₂O), dichloromethane,chloroform, ethyl acetate, hexane, benzene, toluene, xylenes, dioxane,dimethyl formamide (DMF), pentane, alcohols including, but not limitedto, methanol, ethanol and i-propyl alcohol, and mixtures thereof.Alternatively, a mixture of organic solvent and an aqueous solution isused as a reaction solution.

[0116] Percentage of enantiomeric excess (% ee), which is a measure ofenantioselectivity, is equal to % of one enantiomer (e.g. stereoisomer)minus % of the other enantiomer. Thus for example, if the reactionproduces (R,R) and (S,S) epoxides in 99% and 1%, respectively, theenantiomeric excess percentage (% ee) will be 98%. Preferably, methodsof the present invention provide asymmetric epoxidation of olefins in atleast about 50% ee, more preferably at least about 80% ee, and mostpreferably at least about 90% ee. In another embodiment of the presentinvention, the yield of the epoxide from asymmetric epoxidation of anolefin is at least about 10%, more preferably at least about 50%, andmost preferably at least about 80%.

[0117] The temperature of the reaction can also affect the yield of thereaction and/or enantioselectivity of the epoxide. Generally, a lowerreaction temperature requires a longer reaction time but results inhigher enantioselectivity. Preferably the reaction temperature is lessthan about 100° C., more preferably less than about 30° C., and mostpreferably about 0° C. or less.

[0118] Surprisingly and unexpectedly, present inventors have found thatmethods of the present invention are particularly useful in providing ahigh enantiomeric excess in epoxidation of cis-disubstituted olefins andterminal olefins (i.e., geminal di-substituted olefins or in particularmonosubstituted terminal olefins).

[0119] Asymmetric epoxidation of olefins according to the presentinvention can be performed in a variety of different sequences. Theaddition sequence of the olefin, ketone, oxidizing agent, and base (ifused) can be interchanged depending on the nature of each components.Typically, however, a solution comprising an oxidizing agent and aseparate base solution or a solid oxidizing agent and a solid base areadded to a solution comprising the ketone and the olefin. Areverse-addition technique can also be used depending upon thereactivity of each component. A reverse-addition is where the solutioncomprising the ketone is added to the solution comprising the oxidizingagent or to a solid oxidizing agent. Preferably, the initialconcentration of the olefin is from about 0.001 mole/liter (M) to about10 M, more preferably from about 0.02 M to about 1 M.

[0120] Another aspect of the present invention, in some cases, is theease of separation between the epoxide and the ketone. Some epoxidesreadily dissolve and remain in relatively non-polar organic solventssuch as hexane, pentane, and mixtures thereof, whereas the ketoneremains in aqueous solution. Typically the reaction mixture is dilutedwith an extraction solvent to separate the epoxide from the ketone.Additionally, aqueous solution can also be added to the reaction mixtureto further facilitate removal of the ketone from the organic layer.After separating the two layers, the extraction solvent layer comprisingthe epoxide can further be washed with an aqueous solution to furtherremove the ketone that may be present in the extraction solvent layer.This washing can be repeated until substantially all of the ketone isremoved from the extraction solvent layer. Conversely, the aqueous layercan be further washed with the extraction solvent to further obtain theepoxide that may be present in the aqueous layer. Again, this extractioncan be repeated until substantially all the epoxide has been obtained.The epoxide which is separated from the ketone can further be purifiedby any of the current separation methods such as chromatography,distillation, and crystallization.

[0121] The asymmetric epoxidation methods of the present invention areenvironmentally friendly. Water can be used as a co-solvent and unlikeother current asymmetric epoxidation no toxic metals are involved.Therefore, no special disposal method is required, which significantlyreduces the overall cost of the present invention.

[0122] Additional objects, advantages, and novel features of thisinvention will become apparent to those skilled in the art uponexamination of the following examples thereof, which are not intended tobe limiting.

EXAMPLES

[0123] General Methods

[0124] Oxone was purchased from Aldrich (it has been found that theoxidation activity of the purchased Oxone occasionally varies withdifferent batches). All glassware used for the epoxidation was carefullywashed to be free of any trace metals which catalyze the decompositionof Oxone. Elemental analyses were performed by M-H—W Laboratories,Phoenix, Ariz.

Example 1

[0125] This example illustrates a method for synthesizing a variety ofchiral ketones of Formaul XII of the present invention starting from areadily available D-fructose.

[0126] Preparation of Ketone XIIa

[0127] To a solution of alcohol 1a (2.6 g, 10 mmol) (Wang, Z -X.; Tu,Y.; Frohn, M.; Zhang, J -R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224)in CH₂Cl₂ (15 mL) were added Et₃N (5 mL, 30 mmol) and PhCOCl (1.7 g, 12mmol). Upon stirring at rt until no starting material was left as judgedby TLC, the reaction mixture was poured into water, extracted with Et₂O,washed with brine, dried (Na₂SO₄), filtered, concentrated, and purifiedby flash chromatography to give compound 1b (3.39 g, 93%).

[0128] To a solution of compound 1b (0.364 g, 1 mmol) in CH₃CN/H₂O (3.4mL, 9/1) was added DDQ (0.0227 g, 0.1 mmol). Upon stirring at rt for 24h, the reaction mixture was concentrated and purified by flashchromatography to give diol 1c (0.297 g, 92%).

[0129] To a refluxing mixture of diol 1c (2.5 g, 7.72 mmol), PPh₂ (7.69g, 29.32 mmol), imidazole (3.78 g, 55.56 mmol) and zinc (0.031 g) intoluene (37 mL) was added I₂ (3.92 g, 15.43 mmol) over 45 min. After thereaction mixture was stirred at refluxing for another 1 h, another batchof zinc (0.031 g) was added. Upon stirring for additional 3.5 h, thereaction mixture was cooled down, filtered, concentrated, and purifiedby flash chromatography to give compound 1d (1.77 g, 79%).

[0130] To a solution of compound 1d (24.56 g, 84.69 mmol) in methanol(423 mL) was added K₂CO₃ (23.41 g, 169 mmol). Upon stirring at rt for 12h, the reaction mixture was filtered, concentrated, and purified byflash chromatography to give the alcohol (10.78 g, 68%).

[0131] To a solution of the above alcohol (23.52 g, 126 mmol) in DMF(130 mL) were added imidazole.(17.22 g, 253 mmol) and TBDMSCl (28.58 g,190 mmol) at rt. Upon stirring for 24 h., the reaction mixture wasquenched with water, extracted with EtOAc, washed with brine, dried(Na₂SO₄), filtered, concentrated, and purified by flash chromatographyto give compound 1e (32.69 g, 86%).

[0132] To a solution of compound 1e (2.16 g, 7.2 mmol) in CH₃CN/H₂O (14mL, 1/1) were added chloramine-T trihydrate (2.44 g, 8.64 mmol) andK₂OsO₆H₄ (0.018 g, 0.036 mmol). After the mixture was stirred at rtovernight, Na₂SO₃ and EtOAc were added. Upon stirring for an additional1 h, the layers were separated. The organic layer was dried (Na₂SO₄),filtered, concentrated, and purified by flash chromatography to givecompound 1f (3.09 g, 91%).

[0133] To a solution of compound if (0.50 g, 1.062 mmol) and pyridine(0.84 g, 10.62 mmol) in CH₂Cl₂ (5 mL) at 0° C. was added triphosgene(0.315 g, 1.062 mmol). Upon stirring at 0° C. for 4 h, the reactionmixture was quenched with water, extracted with EtOAc, dried (Na₂SO₄),filtered, concentrated, and purified by flash chromatography to givecompound 1g (0.442 g, 84%).

[0134] To a solution of sulfonamide 1g (26.57 g, 51.79 mmol) in THF (52mL) and liquid ammonia (450 mL) at −78° C. was added Li (3.60 g, 518.0mmol). Upon stirring at −78° C. overnight, the reaction mixture wasquenched with solid NH₄Cl and warmed to evaporate NH₃. The resultingmixture was diluted with MeOH, filtered, concentrated, and purified byflash chromatography to give compound 1h (11.91 g, 64%).

[0135] To a solution of compound 1h (0.8 g, 2.23 mmol) in THF (20 mL)was added TBAF (2.23 mL, 2.23 mmol, 1.0 M in THF) at rt under N₂. Themixture was stirred until no starting material was left as judged byTLC. Upon concentration, the mixture was purified by flashchromatography to give the alcohol (0.19 g, 35%).

[0136] To a mixture of the above alcohol (0.19 g, 0.776 mmol) andpowdered 3 Å MS (0.72 g) in CH₂Cl₂ (3.5 mL) was added PCC (0.384 g,1.781 mmol) portionwise over 15 min. Upon stirring at rt under N₂ for 3h, the reaction mixture was filtered through celite and washed withEt₂O. The filtrate was concentrated and purified by flash chromatographyto give ketone XIIa (0.14 g, 74%).

[0137] Preparation of Ketone XIIb

[0138] To a solution of compound 1h (0.064 g, 0.178 mmol) in THF (2 mL)was added NaH (0.009 g, 0.214 mmol) at 0° C. under N₂. After thereaction mixture was stirred at 0° C. for 0.5 h, MeI (0.05 g, 0.356mmol) was added. Upon stirring for another 2 h at rt., the reaction wasquenched with water, extracted with EtOAc, washed with brine, dried(Na₂SO₄), filtered, concentrated, purified by flash chromatography togive compound 1i (0.064 g, 97%).

[0139] To a solution of compound 1i (0.315 g, 0.845 mmol) in THF (10 mL)was added TBAF (0.85 mL, 0.85 mmol, 1.0M in THF) at rt under N₂. Uponstirring until no starting material was left, the reaction mixture wasconcentrated and purified by flash chromatography to give alcohol 1j(0.199 g, 91%).

[0140] To a mixture of alcohol 1j (0.199 g, 0.77 mmol) and powdered 3 ÅMS (0.72 g) in CH₂Cl₂ (3.8 mL) was added PCC (0.385 g, 1.79 mmol)portionwise over 15 min. Upon stirring at rt under N₂ for 3 h, thereaction mixture was filtered through celite and washed with Et₂O. Thefiltrate was concentrated and purified by flash chromatography to giveketone XIIb (0.183 g, 93%).

[0141] Preparation of Ketone XIIc

[0142] To a solution of compound 1h (0.718 g, 2.0 mmol) in THF (10 mL)was added NaH (0.12 g, 3.0 mmol) at 0° C. under N₂. After the reactionmixture was stirred at 0° C. for 0.5 h, BnBr (0.513 g, 3 mmol) wasadded. Upon stirring at rt for another 2 h, the reaction mixture wasquenched with water, extracted with EtOAc, washed with brine, dried(Na₂SO₄), filtered, concentrated, and purified by flash chromatographyto give compound 1k (0.631 g, 70%).

[0143] To a solution of compound 1k (0.598 g, 1.333 mmol) in THF (15 mL)was added TBAF (1.4 mL, 1.4 mmol, 1.0 M in THF) at rt under N₂. Uponstirring until no starting material was left (by TLC), the reactionmixture was concentrated and purified by flash chromatography to givealcohol 1l (0.409 g, 92%).

[0144] To a mixture of alcohol 1l (0.409 g, 1.22 mmol) and powdered 3 ÅMS (1.12 g) in CH₂Cl₂ (5.3 mL) was added PCC (0.605 g, 2.807 mmol)portionwise over 15 min. Upon stirring under N₂ for 3 h, the reactionmixture was filtered through celite and washed with Et₂O. The filtratewas concentrated and purified by flash chromatography to give ketoneXIIc (0.298 g, 73%).

[0145] Preparation of Ketone XIId

[0146] To a mixture of compound 1h (1.017 g, 2.832 mmol) in THF (15 mL)were added Et₃N (0.79 mL, 5.66 mmol), DMAP (0.069 g, 0.566 mmol), and(Boc)₂O (1.236 g, 5.66 mmol). Upon stirring at rt under N₂ for 12 h, thereaction mixture was quenched with water, extracted with EtOAc, dried(Na₂SO₄), filtered, concentrated, and purified by flash chromatographyto give compound 1m (1.35 g, 100%).

[0147] To a solution of compound 1m (1.143 g, 2.49 mmol) in THF (20 mL)was added TBAF (2.5 mL, 2.5 mmol, 1.0 M in THF) at rt under N₂. Uponstirring until no starting material was left as judged by TLC, thereaction mixture was concentrated and purified by flash chromatographyto give alcohol 1n (0.634 g, 74%).

[0148] To a mixture of compound 1n (0.584 g, 1.694 mmol) and powdered 3Å MS (1.6 g) in CH₂Cl₂ (7.3 mL) was added PCC (0.84 g, 3.90 mmol)portionwise over 15 min. Upon stirring at rt under N₂ for 3 h, thereaction mixture was filtered through celite and washed with Et₂O. Thefiltrate was concentrated and purified by flash chromatography to giveketone XIId (0.453 g, 78%).

[0149] Preparation of Ketone XIIe

[0150] To a solution of compound 1h (1.0 g, 2.786 mmol) in THF (20 mL)was added NaH (0.134 g, 3.3 mmol) at 0° C. under N₂. After the reactionmixture was stirred at 0° C. for 0.5 h, BrCH₂CO₂Bu(t) (0.652 g, 3.3mmol) was added. Upon stirring for additional 12 h, the reaction mixturewas quenched with water, extracted with EtOAc, dried (Na₂SO₄), filtered,concentrated, and purified by flash chromatography to give compound 1o(1.26 g, 96%).

[0151] To a solution of compound 1o (1.2 g, 2.54 mmol) in THF (25 mL)was added TBAF (2.55 mL, 2.55 mmol, 1.0 M in THF). Upon stirring at rtuntil no starting material was left as judged by TLC, the reactionmixture was quenched with water, extracted with EtOAc, dried (Na₂SO₄),filtered, concentrated, and purified by flash chromatography to givealcohol 1p (0.876 g, 96%).

[0152] To a solution of alcohol 1p (0.85 g, 2.37 mmol) in CH₂Cl₂ (10 mL)were added 3 Å MS (2.2 g) and PCC (1.2 g, 5.57 mmol). Upon stirring atrt for 12 h, the reaction mixture was passed through a short silica gelcolumn. The filtrate was concentrated and purified by flashchromatography to give ketone XIIe (0.755 g, 89%).

Example 2

[0153] This example illustrates a method for synthesizing a variety ofcompounds of Formula IV.

[0154] Preparation of Aminodiol 2a

[0155] To a suspension of D-glucose (36.0 g, 200.0 mmol) and Bn₂NH (39.5g, 200.0 mmol) in absolute EtOH (200 mL) was added AcOH (12.0 g, 200.0mmol). Upon refluxing for 3 h, the reaction mixture was cooled andfiltered with suction. The resulting filter cake was washed with EtOH tocolorless and dried in a desiccator over calcium chloride to give1-dibenzylamino-1-deoxy-D-fructose as a white solid (57.0 g, 79%).

[0156] To a suspension of 1-dibenzylamino-l-deoxy-D-fructose (2.5 g,6.96 mmol), trimethyl orthoformate (2.0 mL, 18.3 mmol) in acetone (80mL) at 0° C. was added conc: HCl (0.6 mL). Upon stirring at 0° C. for 2h, the reaction mixture was neutralized with NH₄OH, filtered,concentrated, and purified by flash chromatography to give thedibenzylaminodiol as a syrup (2.01 g, 72%): [α]²⁰ _(D)=−87.9 (c, 0.655,CHCl₃); IR (KBr) 3446 cm⁻¹; ¹H NMR δ7.42−7.24 (m, 10H), 4.22−3.91 (m,6H), 3.52−3.48 (m, 2H), 3.30 (d, J=7.5 Hz, 1H), 3.08 (d, J=13.6 Hz, 1H),2.71 (d, J=13.6 Hz, 1H), 1.53 (s, 3H), 1.36 (s, 3H); ¹³C NMR δ138.2,129.2, 128.4, 127.3, 109.0, 96.4, 77.5, 73.7, 72.1, 59.1, 58.8, 56.6,28.2, 26.3. Anal. Calcd for C₂₃H₂₉NO₅: C, 69.15; H, 7.32; N, 3.51.Found: C, 69.38; H, 7.28; N, 3.49.

[0157] A solution of dibenzylaminodiol (15.0 g, 37.41 mmol) in ethanol(250 mL) was purged with N₂, and 10% Pd/C (2.5 g) was added. Uponstirring under H₂ at room temperature overnight, the reaction mixturewas filtered through a short silica gel column and concentrated. Theresulting residue was recrystallized from CH₂Cl₂-hexane in a freezer togive aminodiol 2a as a white crystal (7.25 g, 88%): mp 100-103° C.;[α]²⁰ _(D)=−158.1 (c 0.21, CHCl₃); IR (KBr) 3470, 3361, 1216 cm⁻¹; ¹HNMR δ4.24−4.12 (m, 3H), 3.94 (d, J=13.5 Hz, 1H), 3.47 (d, J=6.9 Hz, 1H),2.95 (d, J=11.7 Hz, 1H), 2.89 (d, J=11.7 Hz, 1H), 1.55 (s, 3H), 1.38 (s,3H); ¹³C NMR δ109.2, 96.2, 77.7, 73.9, 72.5, 59.4, 46.3, 28.4, 26.4.Anal. Calcd for C₉H₁₇NO₅: C, 49.31; H, 7.82; N, 6.39. Found: C, 49.32;H, 7.60; N, 6.20.

[0158] Preparation of Alcohol 2b

[0159] To a solution of 2a (17.15 g, 78.31 mmol) and pyridine (100 mL)in CH₂Cl₂ (350 mL) was added dropwise 4-methoxyphenyl chloroformate(16.07 g, 86.14 mmol) at 0° C. Upon stirring at 0° C. for 5 h, thereaction mixture was quenched with water, extracted with EtOAc, dried(Na₂SO₄), filtered, concentrated, and purified by flash chromatographyto give the carbamate as a colorless oil (24.71 g, 86%): [α]²⁰_(D)=−93.71 (c 0.53, CHCl₃); IR (KBr) 3356, 1719, 1205 cm⁻¹; ¹H NMRδ7.02 (m, 2H), 6.87 (m, 2H), 5.65 (dd, J=7.2, 6.0 Hz, 1H,), 4.23−4.16(m, 3H), 3.99 (d, J=12.9 Hz, 1H), 3.79 (s, 3H), 3.62 (d, J=6.0 Hz, 1H),3.56 (dd, J=14.7, 7.2 Hz, 1H), 3.40 (dd, J=14.7, 6.0 Hz, 1H), 1.55 (s,3H), 1.38 (s, 3H); ¹³C NMR δ157.1, 144.2, 122.4, 114.4, 109.2, 96.7,76.2, 73.3, 70.9, 60.0, 55.7, 47.3, 28.2, 26.1.

[0160] To a solution of the carbamate (10.4 g, 28.01 mmol) in CH₃CN (125mL) was added (CH₃)₃COK (0.38 g, 3.39 mmol). Upon stirring at roomtemperature for 0.5 h, the reaction mixture was concentrated andpurified by flash chromatography to give alcohol 2b as a white solid(6.15 g, 90%): mp 171-173° C.; [α]²⁰ _(D)=−146.25 (c 0.12, CHCl₃); IR(KBr) 3346, 1760, 1077 cm⁻¹; ¹H NMR (CD₃OD) δ4.37−4.34 (m, 1H),4.27−4.21 (m, 2H), 4.10 (d, J=13.8 Hz, 1H), 3.83 (d, J=9.9 Hz, 1H), 3.64(d, J=7.8 Hz, 1H), 3.36 (d, J=9.9 Hz, 1H), 1.53 (s, 3H), 1.40 (s, 3H);¹³C NMR (CD₃OD) δ160.7, 111.2, 107.1,78.6, 75.5, 73.0, 63.3, 50.1, 29.3,27.3. Anal. Calcd for C₁₀H₁₅NO₆: C, 48.98; H, 6.17; N, 5.71.

[0161] Found: C, 49.12; H, 6.15; N, 5.67.

[0162] Preparation of Ketone IVa

[0163] To a mixture of alcohol 2b (1.07 g, 4.37 mmol) and powdered 3 ÅMS (4.0 g) in CH₂Cl₂ (19 mL) was added PCC (2.16 g, 10.02 mmol)portionwise over 15 min. Upon stirring under N₂ for 3 h, the reactionmixture was filtered through celite and washed with Et₂O. The filtratewas concentrated and purified by flash chromatography to give the ketoneIVa as a white solid (0.997 g, 94%): mp 144.5-145.5° C.; [α]²⁰_(D)=−118.0 (c 0.27, CHCl₃); IR (KBr) 3378, 3319, 1759, 1731 cm⁻¹; ¹HNMR (CDCl₃) δ6.51 (s, 1H), 4.84 (d, J=5.4 Hz, 1H), 4.66−4.52 (m, 2H),4.32 (d, J=10.7 Hz, 1H), 4.23 (d, J=13.5 Hz, 1H), 3.38 (d, J=10.7 Hz,1H), 1.46 (s, 3H), 1.42 (s, 3H); ¹³C NMR (CDCl₃) δ195.2, 156.0, 111.0,102.7, 77.5, 75.5, 61.0, 45.3, 27.2, 26.1. HRMS Calcd C₁₀H₁₄NO₆ (M⁺+1):244.0821.

[0164] Found: 244.0824. Anal. Calcd for C₁₀H₁₃NO₆.0.7H₂O: C, 46.95; H,5.67; N, 5.48.

[0165] Found: C,47.16; H,5.86; N,5.43.

[0166] Preparation of TBS Ether 2c

[0167] To a solution of alcohol 2b (10.4 g, 42.45 mmol) in CH₃CN (300mL) were added imidazole (4.33 g, 63.67 mmol) and TBSCl (6.72 g, 44.57mmol). Upon stirring at room temperature for 24 h, the reaction mixturewas quenched with water, extracted with EtOAc, dried (Na₂SO₄), filtered,concentrated, and purified by flash chromatography to give TBS ether 2cas a white solid (10.66 g, 70%): mp 153-155° C.; [α]²⁰ _(D)=−92.92 (c0.12, CHCl₃); IR (KBr) 3286, 1770 cm⁻¹; ¹H NMR δ5.87 (s, 1H), 4.31−4.18(m, 3H), 4.08 (d, J=12.9 Hz, 1H), 3.68 (d, J=9.3 Hz, 1H), 3.65 (d, J=6.6Hz, 1H), 3.39 (dd, J=9.3, 1.0 Hz, 1H), 1.53 (s, 3H), 1.36 (s, 3H), 0.87(s, 9H), 0.17 (s, 3H, Me), 0.098 (s, 3H); ¹³C NMR δ157.8, 109.3, 104.9,77.0, 73.5, 73.3, 61.9, 48.9, 28.4, 26.4, 25.9, 18.2, −3.7, −5.2. Anal.Calcd for C₁₆H₂₉NO₆Si: C, 53.46; H, 8.13; N, 3.90. Found: C, 53.58; H,7.89; N, 4.03.

[0168] Preparation of Ketone IVb

[0169] To a solution of TBS ether 2c (2.0 g, 5.57 mmol) in THF (20 mL)was added NaH (0.267 g, 6.685 mmol) at 0° C. under N₂. Upon stirring for0.5 h, MeI (1.58 g, 11.14 mmol) was added. After being stirred for 12 h,the reaction mixture was quenched with water, extracted with EtOAc,dried (Na₂SO₄), filtered, concentrated, and purified by chromatographyto give 2d (R=Me) as a white solid (2.04 g, 98%): mp 107-108° C.; [α]²⁰_(D=)−62.5 (c 0.20, CHCl₃); IR (KBr) 1773 cm³¹ ¹; ¹H NMR δ4.37−4.18 (m,3H), 4.09 (d, J=13.2 Hz, 1H), 3.65 (d, J=6.3 Hz, 1H), 3.61 (d, J=9.3 Hz,1H), 3.34 (d, J=9.3 Hz, 1H), 2.87 (s, 3H), 1.54 (s, 3H), 1.37 (s, 3H),0.86 (s, 9H), 0.18 (s, 3H), 0.10 (s, 3H); ¹³C NMR δ156.4, 109.4, 101.5,77.1, 73.6, 73.4, 61.9, 54.8, 30.6, 28.5, 26.5, 25.8, 18.2, −3.7, −5.2.Anal. Calcd for C₁₇H₃₁NO₆Si: C, 54.66; H, 8.37; N, 3.75. Found: C,54.72; H, 8.26; N, 3.70.

[0170] To a solution of TBS ether 2d (R=Me) (2.04 g, 5.47 mmol) in THF(20 mL) was added TBAF (1.0 M in THF) (5.5 mL, 5.5 mmol). Upon stirringat room temperature to the completion as judged by TLC, the reactionmixture was quenched with water, extracted with EtOAc, dried (Na₂SO₄),filtered, concentrated, and purified by flash chromatography to give thealcohol as a white solid (1.42 g, 99%). mp 144-146° C.; [α]²⁰_(D)=−158.8 (c 0.08, CHCl₃); IR (KBr) 3422, 1747 cm⁻¹; ¹H NMR δ4.31−4.23(m, 3H), 4.10 (d, J=12.9 Hz, 1H), 3.82 (d, J=9.6 Hz, 1H), 3.71−3.65 (m,1H), 3.36 (d, J=9.6 Hz, 1H), 2.99−2.93 (m, 1H), 2.90 (s, 3H), 1.55 (s,3H), 1.39 (s, 3H); ¹³C-NMR δ156.3, 110.0, 101.4, 76.7, 73.4, 71.8, 61.8,54.6, 30.8, 28.3, 26.2. Anal. Calcd for C₁₁H₁₇NO₆: C, 50.96; H, 6.61; N,5.40.

[0171] Found: C, 50.77; H, 6.40; N, 5.30.

[0172] To a solution of the above alcohol (0.145 g, 0.56 mmol) in CH₂Cl₂(5 mL) were added PDC (0.32 g, 0.84 mmol), 3 Å MS (0.5 g), and AcOH (1drop). Upon stirring at room temperature for 6 h, EtOAc was added. Theresulting mixture was passed through a short silica gel plug,concentrated, and purified by flash chromatography to give ketone IVb(0.144 g, 99%): [α]²⁰ _(D)=−50.7 (c 0.22, CHCl₃); IR (KBr) 3402, 1749cm³¹ ¹; ¹H NMR δ4.79 (d, J=5.7 Hz, 1H), 4.60−4.50 (m, 2H), 4.23 (d,J=10.2 Hz, 1H), 4.18 (d, J=13.5 Hz, 1H), 3.27 (d, J=10.5 Hz, 1H), 2.91(s, 3H), 1.42 (s, 3H), 1.38 (s, 3H); ¹³C NMR δ195.2, 154.2, 111.0, 96.6,77.5, 75.5, 60.9, 50.9, 30.8, 27.2, 26.1. HRMS calcd forC₁₁H₁₆NO₆(M⁺+1): 258.0978. Found: 258.0979.

[0173] Preparation of Ketone IVc

[0174] TBS ether 2d (R=Bn) was prepared from 5(2.0 g, 5.57 mmol) in away similar to 2d (R=Me): white solid (2.49 g, 99%); mp 101-103° C.;[α]²⁰ _(D)=−64.8 (c 0.16, CHCl₃); IR (KBr) 1769 cm⁻¹; ¹H NMR δ7.46−7.23(m, 5H), 4.49 (d, J=15.0 Hz, 1H), 4.35 (d, J=15.0 Hz, 1H), 4.31−4.18 (m,3H), 4.06 (d, J=13.5 Hz, 1H), 3.61 (d, J=6.6 Hz, 1H), 3.52 (d, J=9.3 Hz,1H), 3.20 (d, J=9.3 Hz, 1H), 1.50 (s, 3H), 1.35 (s, 3H), 7.09 (s, 9H),0.14 (s, 3H), −0.00 (s, 3H); ¹³C NMR δ156.4, 135.4, 129.1, 128.4, 128.2,109.4, 102.0, 77.2, 73.4, 73.2, 61.7, 52.1, 48.2, 28.4, 26.4, 25.9,18.1, −3.7, −5.2; Anal. Calcd for C₂₃H₃₅NO₆Si: C, 61.44; H, 7.85; N,3.12. Found: C, 61.30; H, 7.70; N, 3.09.

[0175] TBS ether 2d (R=Bn) (2.49 g, 5.55 mmol) was desilylated in a waysimilar to 2d (R=Me) to give the alcohol as a white solid (1.79 g, 96%):mp 171-172° C.; [α]²⁰ _(D)=−171.4 (c 0.08, CHCl₃); IR (KBr) 3402, 1751cm⁻¹; ¹H NMR δ7.40−7.23 (m, 5H), 4.46 (s, 2H), 4.33−4.21 (m, 3H), 4.10(d, J=12.9 Hz, 1H), 3.67 (d, J=9.6 Hz, 1H), 3.68−3.61 (m, 1H), 3.25 (d,J=9.6 Hz, 1H), 1.50 (s, 3H), 1.37 (s, 3H). Anal. Calcd for C₁₇H₂₁NO₆: C,60.89; H, 6.31; N, 4.18. Found: C, 60.90; H, 6.13; N4.14.

[0176] The above alcohol (0.041 g, 0.122 mmol) was oxidized with PDC togive ketone IVc as a white solid (0.038 g, 93%): mp 176-178° C.; [α]²⁰_(D)=−85.7 (c 0.15, CHCl₃); IR (KBr) 3394, 1756 cm⁻¹; ¹H NMR δ7.36−7.13(m, 5H), 4.74 (d, J=5.7 Hz, 1H), 4.57−4.30 (m, 4H), 4.12 (d, J=13.2 Hz,1H), 4.05 (d, J=10.2 Hz, 1H), 3.10 (d, J=10.2 Hz, 1H), 1.34 (s, 3H),1.33 (s, 3H); ¹³C NMR δ195.1, 154.2, 134.6, 129.0, 128.3, 128.0, 111.0,100.0, 77.5, 75.5, 61.0, 48.5, 48.2, 27.2, 26.1. Anal. Calcd forC₁₇H₁₉NO₆.0.4H₂O: C, 59.96; H, 5.82; N 4.12. Found: C, 59.78; H, 5.89; N4.16.

[0177] Preparation of Ketone IVd

[0178] To a solution of TBS ether 2c (2.0 g, 5.57 mmol) in THF (20 mL)were added Et₃N (2.82 g, 27.86 mmol), DMAP (0.136 g, 1.11 mmol), and(Boc)₂O (2.43 g, 11.14 mmol). Upon stirring at room temperature for 24h, the reaction mixture was quenched with water, extracted with EtOAc,dried (Na₂SO₄), filtered, concentrated, and purified by flashchromatography to give TBS ether 2d (R=Boc) as a white solid (2.53 g,99%/O): mp 114-115 ° C.; [α]²⁰ _(D)=−67.7 (c 0.118, CHCl₃); IR (KBr)1828, 1808, 1727 cm⁻¹; ¹H NMR δ4.27−4.08 (m, 4H), 3.94 (d, J=10.8 Hz,1H), 3.68 (d, J=10.8 Hz, 1H), 3.65 (d, J=6.9 Hz, 1H), 1.52 (s, 3H), 1.50(s, 9H), 0.84 (s, 9H), 0.17 (s, 3H), 0.11 (s, 3H); ¹³C NMR δ150.3,148.8, 109.4, 101.1, 84.0, 76.8, 73.8, 73.1, 62.3, 51.8, 28.4, 28.1,26.4, 25.8, 18.1, −3.7, −5.3; Anal. Calcd for C₂₃H₃₇NO₈Si: C, 54.88; H,8.11; N, 3.05. Found: C, 54.77; H, 7.98; N, 3.05.

[0179] To a solution of TBS ether 2d (R=Boc) (6.43 g, 14.0 mmol) in THF(100 mL) was added Et₃N.3HF (22.6 g, 140.0 mmol). Upon stirring at roomtemperature to the completion as judged by TLC (about 4 days), thereaction mixture was quenched with water, extracted with EtOAc, dried(Na2SO₄), filtered, concentrated, and purified by flash chromatographyto give the alcohol as a white solid (4.47 g, 93%): mp 120.0-121.5° C.;[α]²⁰ _(D)=−113.9(c 0.33, CHCl₃); IR (KBr) 3481, 1812, 1733, 1718, 1222,1162cm⁻¹; ¹H NMR δ4.26−4.23 (m, 3H), 4.13 (d, J=11.2 Hz, 1H), 4.12 (d,J=12.8 Hz, 1H), 3.75 (d, J=11.2 Hz, 1H), 3.76−3.70 (m, 1H), 2.74 (d,J=6.8 Hz, 1H, OH), 1.53 (s, 3H), 1.52 (s, 9H), 1.37 (s, 3H); ¹³C NMRδ150.5, 148.9, 109.9, 101.0, 84.3, 76.4, 73.1, 71.2, 62.0, 51.4, 28.2,28.1, 26.2.

[0180] The above alcohol (1.9 g, 5.51 mmol) was oxidized with PDC togive ketone IVd as a white solid (1.52 g, 80%): mp 139-140° C.; [α]²⁰_(D)=−47.9 (c 0.83, CHCl₃); IR (KBr): 3446 (hydrate), 1823, 1756,1731cm⁻¹; ¹H NMR δ4.79 (d, J=5.6 Hz, 1H), 4.61 (dd, J=5.6, 1.8 Hz, 1H), 4.56(d, J=11.6 Hz, 1H), 4.51 (dd, J=13.6, 1.8 Hz, 1H), 4.23 (d, J=13.6 Hz,1H), 3.71 (d, J=11.6 Hz, 1H), 1.53 (s, 9H), 1.45 (s, 3H), 1.41 (s, 3H);¹³C NMR δ194.9, 149.0, 148.6, 111.3, 98.9, 85.0, 77.4, 75.5, 61.3, 48.4,28.0, 27.2, 26.0; Anal. Calcd for C₁₅H₂₁NO₈: C, 52.47; H, 6.17; N, 4.08.Found: C, 52.32; H, 5.94; N, 3.97.

[0181] Preparation of Ketone IVe

[0182] To a solution of TBS ether 2c (0.718 g, 2.0 mmol) in THF (20 mL)were added Et₃N (1.0 g, 10.0 mmol), DMAP (0.024 g, 0.2 mmol), andPhOCOCl (0.47 g, 3.0 mmol) at 0° C. under N₂. Upon stirring to thecompletion as judged by TLC (about 2 h), the reaction mixture wasquenched with water, extracted with EtOAc, dried (Na₂SO₄), filtered,concentrated, and purified by flash chromatography to give compound 2d(where R is —C(═O)OPh) as a white solid (0.95 g, 99%): mp 123-125° C.;[α]²⁰ _(D)=−47.6(c 1.19, CHCl₃); IR (KBr) 1839, 1806, 1743 cm⁻¹; ¹H NMRδ7.47−7.41 (m, 2H), 7.33−7.29 (m, 1H), 7.20−7.17 (m, 2H), 4.37−4.19 (m,4H), 4.19 (d, J=11.0 Hz, 1H), 3.95 (d, J=11.0 Hz, 1H), 3.77 (d, J=6.9Hz, 1H), 1.59 (s, 3H), 1.43 (s, 3H), 0.94 (s, 9H), 0.25 (s, 3H), 0.19(s, 3H); ¹³C NMR δ150.0, 149.8, 149.0, 129.7, 126.6, 121.4, 109.6,101.9, 76.8, 73.9, 73.0, 62.6, 52.1, 28.5, 26.5, 25.9, 18.2, −3.9, −5.2.

[0183] TBS ether 2d (where R is —C(═O)OPh) (0.63 g, 1.32 mmol) wasdesilylated with Et₃N.3HF (1.06 g, 6.58 mmol) in a way similar to 2d(where R is Boc) to give the alcohol as a white solid (0.372 g, 78%)(about 3 days): mp 185-186° C.; [α]²⁰ _(D)=−101.8° (c 1.02, CHCl₃); IR(KBr) 3474, 1829, 1744 cm⁻¹; ¹H NMR δ7.39−7.32 (m, 2H), 7.26−7.19 (m,1H), 7.17−7.12 (m, 2H), 4.32−4.11 (m, 5H), 3.92 (d,J=10.8 Hz, 1H), 3.76(m, 1H), 2.99 (s, 1H), 1.51 (s, 3H), 1.36 (s, 3H); ¹³C NMR δ150.0,149.0, 129.6, 126.6, 121.4, 110.1, 101.7, 76.3, 73.0, 71.4, 62.4, 51.7,28.3, 26.3. Anal. Calcd for C₁₇H₁₉NO₈: C, 55.89; H, 5.24; N, 3.83.Found: C, 56.03; H, 5.40; N, 3.95.

[0184] The above alcohol (0.255 g, 0.70 mmol) was oxidized with PDC togive ketone IVe as a white solid (0.25 g, 96%): mp: 190-191° C.; [α]²⁰_(D)=−55.0° (c 0.93, CHCl₃); IR (KBr) 1843, 1759, 1720 cm⁻¹; ¹H NMRδ7.45−7.38 (m, 2H), 7.32−7.26 (m, 1H), 7.22−7.18 (m, 2H), 4.83 (d, J=5.4Hz, 1H), 4.78 (d, J=11.5 Hz, 1H), 4.65 (m, 1H), 4.55 (dd, J=13.7, 2.1Hz, 1H), 4.29 (d, J=13.7 Hz, 1H), 3.95 (d, J=11.5 Hz, 1H), 1.48 (s, 3H),1.44 (s, 3H); ¹³C NMR δ194.5, 149.9, 148.4, 129.7, 126.8, 121.3, 111.5,99.5, 77.3, 75.4, 61.7, 48.8, 27.3, 26.2. Anal. Calcd for C₁₇H₁₇NO₈: C,56.20; H, 4.72; N, 3.86. Found: C, 56.12; H, 4.73; N, 3.82.

[0185] Preparation of Ketone IVf

[0186] To a solution of 2c (0.718 g, 2.0 mmol) in THF (20 mL) was addedEt₃N (2.02 g, 20.0 mmol), DMAP (0.024 g, 0.2 mmol), and Me₂NCOCl (0.43g, 4.0 mmol) at 0° C. under N₂. Upon stirring to the completion asjudged by TLC (about 12 h), the reaction mixture was quenched withwater, extracted with EtOAc, dried (Na2SO₄), filtered, concentrated, andpurified by flash chromatography to give compound 2d (where R is—C(═O)NMe₂) as a white solid (0.83 g, 96%): mp 129-131° C.; [α]²⁰_(D)=−85.0° (c 0.81, CHCl₃); IR (KBr) 1782, 1688 cm⁻¹; ¹H NMR δ4.26−4.05(m, 5H), 3.71−3.68 (m, 2H), 2.99 (s, 6H), 1.52 (s, 3H), 1.35 (s, 3H),0.86 (s, 9H), 0.16 (s, 3H), 0.11 (s, 3H); ¹³C NMR δ152.8, 152.1, 109.4,102.7, 76.8, 73.0, 72.8, 62.0, 51.7, 28.2, 26.3, 25.9, 18.2, −3.8, −5.1.

[0187] TBS ether 2d (where R is —C(═O)NMe₂) (0.617 g, 1.435 mmol) wasdesilylated with Et₃N.3HF (2.31 g, 14.35 mmol) in a way similar to 2d(where R is Boc) to give the alcohol as a white solid (0.346 g, 76%)(about 3 days): mp 167-169° C.; [α]²⁰ _(D)=−102.3° (c 0.87, CHCl₃); IR(KBr) 3428, 1783, 1683 cm⁻¹; ¹H NMR δ4.31 (d, J=10.4 Hz, 1H), 4.28−4.23(m, 3H), 4.12 (d, J=13.5 Hz, 1H), 3.78 (m, 1H), 3.66 (d, J=10.4 Hz, 1H),3.20 (bs, 1H), 3.01 (s, 6H), 1.54 (s, 3H), 1.38 (s, 3H); ¹³C NMR δ153.0,152.0, 109.9, 102.6, 76.2, 73.0, 71.2, 62.2, 51.7, 28.2, 26.2.

[0188] The above alcohol (0.217 g, 0.687 mmol) was oxidized with PDC togive ketone IVf as a white solid (0.204 g, 95%): mp 115-117° C.; [α]²⁰_(D)=−72.3 (c 1.11, CHCl₃); IR (KBr) 3409, 1789, 1760, 1688 cm⁻¹; ¹H NMRδ4.80 (d, J=5.4, 1H), 4.65−3.94 (m, 4H), 3.70 (d, J=11.1 Hz, 1H), 3.03(s, 6H), 1.47 (s, 3H), 1.41 (s, 3H). Anal. Calcd for C₁₃H₁₈N₂O₇.0.4H₂O:C, 48.56; H, 5.85; N, 8.72. Found: C, 48.85; H, 5.97; N8.46.

[0189] Preparation of Ketone 2g

[0190] To a solution of 2c (0.718 g, 2.0 mmol) in THF (20 mL) were addedEt₃N (1.0 g, 10.0 mmol), DMAP (0.024 g, 0.2 mmol), and CH₃COCl (0.236 g,3.0 mmol) at 0° C. under N₂. Upon stirring to the completion as judgedby TLC (about 12 h), the reaction mixture was quenched with water,extracted with EtOAc, dried (Na₂SO₄), filtered, concentrated, andpurified by flash chromatography to give compound 2d (where R is—C(═O)CH₃) as a white solid (0.727 g, 91%): mp 76-78° C.; [α]²⁰_(D)=−64.0 (c 0.97, CHCl₃); IR (KBr) 1794, 1709 cm⁻¹; ¹H NMR δ4.28−4.13(m, 4H), 3.99 (d, J=11.5 Hz, 1H), 3.76 (d, J=11.5 Hz, 1H), 3.69 (d,J=6.9 Hz, 1H), 2.50 (s, 3H), 1.55 (s, 3H), 1.38 (s, 3H), 0.83 (s, 9H),0.19 (s, 3H), 0.10 (s, 3H); ¹³C NMR δ169.9, 151.9, 109.6, 102.2, 76.8,73.9, 73.0, 62.6, 51.2, 28.5, 26.5, 25.8, 23.7, 18.1, −3.6, −5.2. Anal.Calcd for C₁₈H₃₁NO₇Si: C, 53.84; H, 7.78; N, 3.49. Found: C, 54.03; H,7.74; N, 3.41.

[0191] TBS ether 2d (where R is —C(═O)CH₃) (0.65 g, 1.62 mmol) wasdesilylated with Et₃N.3HF (0.523 g, 3.24 mmol) in a way similar to 2d(where R is Boc) to give the alcohol as a colorless oil (0.267 g, 57%)(about 5 days): [α]²⁰ _(D)=−143.2 (c 0.9, CHCl₃); IR (KBr) 3447, 1793,1709 cm⁻¹; ¹H NMR δ4.28−4.17 (m, 4H), 4.15 (d, J=11.7 Hz, 1H), 3.82 (d,J=11.7 Hz, 1H), 3.75 (d, J=5.7 Hz, 1H), 3.21 (s, 1H), 2.51 (s, 3H), 1.54(s, 3H), 1.38 (s, 3H); ¹³C NMR δ170.2, 151.9, 110.1, 101.9, 76.4, 73.1,71.4, 62.3, 50.6, 28.3, 26.3, 23.8. Anal. Calcd for C₁₂H₁₇NO₇: C, 50.17;H, 5.96; N, 4.88. Found: C, 50.09; H, 5.70; N, 4.77.

[0192] The above alcohol (0.18 g, 0.627 mmol) was oxidized with PDC togive ketone IVg as a colorless oil (0.177 g, 99%): [α]²⁰ _(D)=−56.8 (c2.77, CH₃CN); IR (KBr) 3427 (hydrate), 1798, 1711 cm⁻¹; Ketone: ¹H NMR(CD₃CN) δ4.85 (d, J=6.0 Hz, 1H), 4.43−4.15 (m, 3H), 3.71 (d, J=12.3 Hz,1H), 3.61 (d, J=12.3 Hz, 1H), 2.40 (s, 3H), 1.47 (s, 3H), 1.40 (s, 3H);¹³C NMR (CD₃CN) δ196.3, 170.5, 152.4, 111.7, 103.1, 78.2, 76.1, 62.8,48.9, 27.2, 26.0, 23.7; Hydrate: ¹H NMR (CD₃CN) δ4.67 (d, J=5.1 Hz, 1H),4.43−4.15 (m, 4H), 3.81 (d, J=12.7 Hz, 1H), 2.40 (s, 3H), 1.36 (s, 3H),1.33 (s, 3H); ¹³C NMR (CD₃CN) δ170.5, 151.5, 110.5, 100.4, 92.0, 76.6,73.8, 64.5, 51.6, 26.5, 24.8, 23.8. HRMS calcd for C₁₂H₁₈NO₈ (M.H₂0 +1):304.1032. Found: 304.1026.

[0193] Preparation of Ketone IVh

[0194] To a solution of 2c (0.718 g, 2.0 mmol) in CH₂Cl₂ (20 mL) wereadded Et₃N (1.0 g, 10.0 mmol), DMAP (0.024 g, 0.2 mmol), and Me₃CCOCl(0.326 g, 3.0 mmol) at 0° C. under N₂. Upon stirring to the completionas judged by TLC (about 12 h), the reaction mixture was quenched withwater, extracted with EtOAc, dried (Na₂SO₄), filtered, concentrated, andpurified by flash chromatography to give compound 2d (where R is—C(═O)C(CH₃)₃) as a white solid (0.884 g, 99%): mp 145-148° C.; [α]²⁰_(D)=−59.2 (c 1.35, CHCl₃); IR (KBr) 1789, 1687 cm⁻¹; ¹H NMR (CDCl₃)δ4.30−4.11 (m, 4H), 4.04 (d, J=11.9 Hz, 1H), 3.79 (d, J=11.9 Hz, 1H),3.67 (d, J=6.9 Hz, 1H), 1.54 (s, 3H), 1.37 (s, 3H), 1.36 (s, 9H), 0.83(s, 9H), 0.18 (s, 3H), 0.10 (s, 3H); ¹³C NMR δ177.9, 150.4, 109.6,101.6, 76.9, 73.6, 73.1, 62.2, 53.4, 41.6, 28.5, 26.5, 26.4, 25.9, 18.2,−3.6, −5.2. Anal. Calcd for C₂₁H₃₇NO₇Si: C, 56.86; H, 8.41; N, 3.16.Found: C, 57.00; H, 8.35; N, 3.23.

[0195] TBS ether 2d (where R is —C(═O)C(CH₃)₃) (0.75 g, 1.69 mmol) wasdesilylated with Et₃N.3HF (0.546 g, 3.39 mmol) in a way similar to 2d(where R is Boc) to give the alcohol as a colorless oil (0.506 g, 91%)(about 5 days): [α]²⁰ _(D)=−64.2 (c 1.15, CHCl₃); IR (KBr) 3458, 1793,1691 cm⁻¹; ¹H NMR δ4.28−4.12 (m, 5H), 3.84 (d, J=11.7 Hz, 1H), 3.74 (d,J=5.7 Hz, 1H), 3.06 (bs, 1H), 1.54 (s, 3H), 1.38 (s, 3H), 1.37 (s, 9H);¹³C NMR δ178.2, 150.5, 110.1, 101.4, 76.4, 73.1, 71.4, 62.1, 53.1, 41.6,28.3, 26.4, 26.2. Anal. Calcd for C₁₅H₂₃NO₇: C, 54.70; H, 7.04; N, 4.25.Found: C, 54.70; H, 7.11; N, 4.14.

[0196] The above alcohol (0.40 g, 1.22 mmol) was oxidized with PDC togive ketone IVh as a white solid (0.372 g, 94%): mp 156-157° C.; [α]²⁰_(D)=−40.4 (c 1.95, CHCl₃); IR (KBr) 3468 (hydrate), 1799, 1758, 1697cm⁻¹; ¹H NMR 6 4.78 (d, J=5.4 Hz, 1H), 4.62 (dd, J=5.4, 1.8 Hz, 1H),4.58 (d, J=12.6 Hz, 1H), 4.48 (dd, J=13.5, 1.8 Hz, 1H), 4.23 (d, J=13.5Hz, 1H), 3.82 (d, J=12.6 Hz, 1H), 1.47 (s, 3H), 1.41 (s, 3H), 1.37 (s,9H); ¹³C NMR δ194.8, 177.7, 149.0, 111.5, 99.5, 77.7, 75.4, 61.6, 50.3,41.7, 27.3, 26.3, 26.2. Anal. Calcd for C₁₅H₂₁NO₇: C, 55.04; H, 6.47; N,4.28. Found: C, 55.22; H, 6.31; N, 4.32.

[0197] Preparation of Ketone IVi

[0198] To a solution of 2c (0.718 g, 2.0 mmol) in THF (20 mL) were addedEt₃N (1.0 g, 10.0 mmol), DMAP (0.024 g, 0.2 mmol), and PhCOCl (0.422 g,3.0 mmol) at 0 ° C. under N₂. Upon stirring to the completion as judgedby TLC (about 12 h), the reaction mixture was quenched with water,extracted with EtOAc, dried (Na₂SO₄), filtered, concentrated, andpurified by flash chromatography to give compound 2d (where R is—C(═O)CPh) as a white solid (0.867g, 94%): mp 93-95° C.; [α]²⁰_(D)=−84.7 (c 1.22, CHCl₃); IR (KBr) 1796, 1685 cm⁻¹; ¹H NMR δ7.68−7.44(m, 5H), 4.35−4.19 (m, 5H), 4.00 (d, J=11.4 Hz, 1H), 3.81 (d, J=6.6 Hz,1H), 1.61 (s, 3H), 1.42 (s, 3H), 0.93 (s, 9H), 0.25 (s, 3H), 0.19 (s,3H); ¹³C NMR δ169.0, 151.2, 132.8, 132.3, 130.2, 129.2, 129, 127.9, 109.6,102. 2,76.8, 73.6, 73.1, 62.5, 51.7, 28.4, 26.4, 26.0, 18.3, −3.6,−5.1.

[0199] TBS ether 2d (where R is —C(═O)CPh) (0.64 g, 1.382 mmol) wasdesilylated with Et₃N.3HF (0.569 g, 3.529 mmol) in a way similar to 2d(where R is Boc) to give the alcohol as a white solid (0.448 g, 93%/0)(about 3 days): mp 120-123° C.; [α]²⁰ _(D)=−134.1 (c 1.09, CHCl₃); IR(KBr) 3444, 1794, 1685 cm⁻¹; ¹H NMR δ7.67−7.41 (m, 5H), 4.43−4.17 (m,5H), 3.97 (d, J=11.7 Hz, 1H), 3.81 (d, J=6.6 Hz, 1H), 3.06 (bs, 1H),1.56 (s, 3H), 1.40 (s, 3H); ¹³C NMR δ169.3, 151.4, 132.5, 129.1, 128,110.1, 102.1, 76.3, 73.0, 71.4, 62.4, 51.5, 28.3, 26.2. Anal. Calcd forC₁₇H₁₉NO₇: C, 58.45; H, 5.48; N, 4.01. Found: C, 58.38; H, 5.46; N,3.95.

[0200] The above alcohol (0.326 g, 0.935 mmol) was oxidized with PDC togive ketone IVi as a white solid (0.307 g, 95%/): mp 66-68° C.; [α]²⁰_(D)=−91.2 (c 1.06, CHCl₃); IR (KBr) 3452 (hydrate), 1799, 1687 cm⁻¹; ¹HNMR 8 7.69−7.43 (m, 5H), 4.81 (d, J=6.3 Hz, 1H), 4.78 (d, J=12.5 Hz,1H), 4.65 (m, 1H), 4.51 (dd, J=13.8, 2.1 Hz, 1H), 4.29 (d, J=13.8 Hz,1H), 3.98 (d, J=12.5 Hz, 1H), 1.51 (s, 3H), 1.44 (s, 3H); ¹³C NMRδ194.7, 168.8, 150.0, 132.8, 132.2, 129.2, 128.1, 111.6, 99.9, 77.2,75.4, 61.9, 48.9, 27.3, 26.2. Anal. Calcd for C₁₇H₁₇NO₇: C, 58.79; H,4.93; N, 4.03. Found: C, 58.78; H, 5.12; N, 4.00.

[0201] Preparation of Ketone IVj

[0202] To a solution of 2c (0.718 g, 2.0 mmol) in THF (20 mL) were addedEt₃N (2.6 mL, 20.0 mmol), DMAP (0.024 g, 0.2 mmol), and4-methoxylbenzoyl chloride (0.41 g, 2.4 mmol) at 0° C. under N₂. Uponstirring to the completion as judged by TLC (about 12 h), the reactionmixture was quenched with water, extracted with EtOAc, dried (Na₂SO₄),filtered, concentrated, and purified by flash chromatography to givecompound 2d (where R is —C(═O)C[(4-OMe)Ph]) as a white solid (0.98 g,99%): mp 139.0-140.5° C.; [α]²⁰ _(D)=−75.5 (c 1.78, CHCl₃); IR (KBr)1794, 1680, 1607 cm⁻¹; ¹H NMR δ7.69−7.64 (m, 2H), 6.93−6.89 (m, 2H),4.32−4.15 (m, 4H), 4.22 (d, J=11.4 Hz, 1H), 3.95 (d, J=11.4 Hz, 1H),3.86 (s, 3H), 3.76 (d, J=6.6 Hz, 1H), 1.56 (s, 3H), 1.38 (s, 3H), 0.87(s, 9H), 0.20 (s, 3H), 0.14 (s, 3H); ¹³C NMR δ168.3, 163.1, 151.6,131.8, 124.6, 113.3, 109.6, 102.1, 76.9, 73.5, 73.1, 62.4, 55.6, 51.9,28.5, 26.5, 26.0, 18.3, −3.6, −5.0.

[0203] TBS ether 2d (where R is —C(═O)C[(4-OMe)Ph)](0.746 g, 1.512 mmol)was desilylated with Et₃N.3HF (1.22 g, 7.56 mmol) in a way similar to 2d(where R is Boc) to give the alcohol as a white solid (0.489 g, 85%)(about 3 days): mp 66-68° C.; [α]²⁰ _(D)=−140.3 (c, 0.94, CHCl₃); IR(KBr) 3447, 1793, 1680, 1606 cm⁻¹; ¹H NMR δ7.71−7.66 (m, 2H), 6.94−6.89(m, 2H), 4.41−4.17 (m, 5H), 3.95 (m, 1H), 3.86 (s, 3H), 3.82 (d, J=6.0Hz, 1H), 1.56 (s, 3H), 1.40 (s, 3H); ¹³C NMR δ167.5, 156.9, 150.7,132.6, 128.8, 123.6, 120.6, 111.0, 110.1, 101.8, 76.3, 73.0., 71.6,62.4, 56.0, 51.2, 28.3, 26.2. Anal. Calcd for C₁₈H₂₁NO₈: C, 56.99; H,5.58; N, 3.69. Found: C, 56.76; H 5.74; N, 3.65.

[0204] The above alcohol (0.461 g, 1.216 mmol) was oxidized with PDC togive ketone IVj as a white solid (0.429 g, 94%): mp 63-65° C.; [α]²⁰_(D)=−89.1 (c 0.96, CHCl₃); IR (KBr) 1799, 1758, 1684, 1606 cm⁻¹; ¹H NMRδ7.72−7.69 (m, 2H), 6.96−6.92 (m, 2H), 4.81 (d, J=5.4 Hz, 1H), 4.78 (d,J=12.3 Hz, 1H), 4.65 (m, 1H), 4.52 (dd, J=2.1 Hz, 1H), 4.29 (d, J=13.5Hz, 1H), 3.95 (d, J=12.3 Hz, 1H), 3.87 (s, 3H), 1.51 (s, 3H), 1.44 (s,3H); ¹³C NMR δ194.7, 168.0, 163.5, 150.4, 132.0, 126.8, 124.0, 118.0,113.5, 77.3, 75.5, 61.9, 55.7, 49.1, 27.3, 26.2. Anal. Calcd forC₁₈H₁₉NO₈: C, 57.29; H, 5.08; N, 3.71.

[0205] Found: C, 57.17; H, 5.24; N, 3.61.

[0206] Preparation of Ketone IVk

[0207] To a solution of 2c (0.718 g, 2.0 mmol) in THF (20 mL) were addedEt₃N (2.6 mL, 20.0 mmol), DMAP (0.024 g, 0.2 mmol), and2-methoxylbenzoyl chloride (0.41 g, 2.4 mmol) at 0° C. under N₂. Uponstirring to the completion as judged by TLC (about 12 h), the reactionmixture was quenched with water, extracted with EtOAc, dried (Na₂SO₄),filtered, concentrated, and purified by flash chromatography to givecompound 2d (where R is —C(═O)C[(2-OMe)Ph]) as a white solid (0.9 g,91%): mp 114-116° C.; [α]²⁰ _(D)=−92.0 (c 1.12, CHCl₃); IR (KBr) 1802,1685, 1603 cm⁻¹; ¹H NMR δ7.42 (m, 1H), 7.25 (m, 1H), 7.00 (m, 1H), 6.91(d, J=8.4 Hz, 1H), 4.29−4.12 (m, 5H), 3.96 (d, J=11.7 Hz. 1H), 3.81 (s,3H), 3.75 (d, J=6.6 Hz, 1H), 1.56 (s, 3H), 1.38 (s, 3H), 0.89 (s, 9H),0.19 (s, 3H), 0.15 (s, 3H); ¹³C NMR δ167.4, 156.9, 150.5, 132.2, 128.4,124, 120.5, 111, 109.6, 101.9, 76.8, 73.3, 73.1, 62.3, 55.9, 51.1, 28.4,26.4, 26, 18.3, −3.6, −5.1.

[0208] TBS ether 2d (where R is —C(═O)C[(2-OMe)Ph]) (0.696 g, 1.411mmol) was desilylated with Et₃N.3HF (1.14 g, 7.05 mmol) in a way similarto 2d (where R is Boc) to give the alcohol as a white solid (0.501 g,94%) (about 3 days): mp 68-71° C.; [α]²⁰ _(D)=−119.7 (c 1.01, CHCl₃); IR(KBr) δ3453, 1801, 1684, 1603 cm⁻¹; ¹H NMR δ7.48−7.42 (m, 1H), 7.34 (dd,J=7.8, 1.8 Hz, 1H), 7.01 (t, J=7.8 Hz, 1H), 6.92 (d, J=7.8 Hz, 4.33 (d,J=11.7 Hz, 1H), 4.29−4.15 (m, 4H), 3.99 (d, J=11.7 Hz, 1H), 3.81 (s,3H), 3.84−3.79 (m, 1H), 1.56 (s, 3H), 1.39 (s, 3H); ¹³C NMR δ167.5,156.9, 150.7, 132.6, 128.8, 123.6, 120.6, 111.0, 110.1, 101.8, 76.3,73.0, 71.6, 62.4, 56.0, 51.2, 28.3, 26.2.

[0209] The above alcohol (0.403 g, 1.063 mmol) was oxidized with PDC togive ketone IVk as a white solid (0.391 g, 97%): mp 160-161° C.; [α]²⁰_(D)=−75.0 (c 1.09, CHCl₃); IR (KBr) 3487 (hydrate), 1806, 1758, 1689,1603 cm⁻¹; ¹H NMR δ7.50−7.44 (m, 1H), 7.35 (dd, J=7.4, 1.4 Hz, 1H),7.05−7.00 (m, 1H), 6.93 (d, J=8.4 Hz, 1H), 4.80 (d, J=5.4 Hz, 1H), 4.74(d, J=12.3 Hz, 1H) 4.63 (m, 1H), 4.49 (dd, J=13.8, 2.1 Hz, 1H), 4.27 (d,J=13.8 Hz, 1H), 3.99 (d, J=12.3 Hz, 1H), 3.83 (s, 3H), 1.50 (s, 3H),1.43 (s, 3H); ¹³C NMR δ194.7, 167.1, 156.9, 149.2, 132.7, 128.9, 123.1,120.6, 111.5, 110.9, 99.7, 77.2, 75.4, 61.8, 55.9, 48.4, 27.2, 26.1.Anal. Calcd for C₁₈H₁₉NO₈: C, 57.29; H, 5.08; N, 3.71. Found: C, 57.17;H, 5.18; N, 3.83.

[0210] Preparation of Ketone IVL

[0211] To a solution of 2c (0.718 g, 2.0 mmol) in THF (10 mL) were addedEt₃N (1.01 g, 10.0 mmol), DMAP (0.024 g, 0.2 mmol), and2,4-dimethoxylbenzoyl chloride (0.482 g, 2.4 mmol) at 0° C. under N₂.Upon stirring to the completion as judged by TLC (about 5 h), thereaction mixture was quenched with water, extracted with EtOAc, dried(Na₂SO₄), filtered, concentrated, and purified by flash chromatographyto give compound 2d (where R is —C(═O)C[2,4-(OMe)₂Ph]) as a white solid(0.973 g, 93%): mp 69-70° C.; [α]²⁰ _(D)=−73.8 (c 1.30, CHCl₃); IR (KBr)1799, 1680, 1609 cm⁻¹; ¹H NMR δ7.32−7.29 (m, 1H), 6.54 (dd, J=8.4, 2.1Hz, 1H), 6.48 (d, J=1.8 Hz, 1H), 4.34−4.17 (m, 5H), 3.98 (d, J=11.4 Hz,1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.78 (d, J=6.6 Hz, 1H), 1.60 (s, 3H),1.42 (s, 3H), 0.92 )s, 9H), 0.23 (s, 3H), 0.19 (s, 3H); ¹³C NMR δ167.0,163.4, 159.0, 130.5, 116.5, 109.6, 104.7, 101.8, 98.5, 76.9, 73.3, 73.2,62.3, 55.9, 55.7, 51.3, 28.5, 26.5, 26.0, 18.3, −3.6, −5.1.

[0212] TBS ether 2d (where R is —C(═O)C[2,4-(OMe)₂Ph]) (0.93 g, 1.78mmol) was desilylated with Et3N.3HF (1.43 g, 8.89 mmol) in a way similarto 2d (where R is Boc) to give the alcohol as a white solid (0.67 g,92%) (about 3 days): mp 70-72° C.; [α]²⁰ _(D)=−114.0 (c 1.00, CHCl₃); IR(KBr) 3447, 1797, 1676, 1609 cm⁻¹; ¹H NMR δ7.36 (d, J=8.4 Hz, 1H), 6.52(dd, J=8.4, 2.4 Hz, 1H), 6.44 (d, J=2.4 Hz, 1H), 4.32 (d, J=11.7 Hz,1H), 4.28−4.12 (m, 4H), 3.94 (d, J=11.7 Hz, 1H), 3.84 (s, 3H), 3.79 (m,1H), 3.77 (s, 3H), 1.55 (s, 3H), 1.39 (s, 3H); ¹³C NMR δ167.2, 163.6,159.0, 150.9, 131.0, 116.0, 109.9, 104.8, 101.9, 98.4, 76.2, 73.0, 71.3,62.2, 55.9, 55.6, 51.2, 28.2, 26.2.

[0213] The above alcohol (0.518 g, 1.267 mmol) was oxidized with PDC togive ketone IVl as a white solid (0.44 g, 85%): mp 74-76° C.; [α]²⁰_(D)=−78.0 (c, 1.04, CHCl₃); IR (KBr) 1805, 1758, 1681, 1609 cm⁻¹; ¹HNMR δ7.36 (d, J=8.4 Hz, 1H), 6.53 (dd, J=8.4, 2.4 Hz, 1H), 6.44 (d,J=2.1 Hz, 1H), 4.80 (d, J=6.0 Hz, 1H), 4.72 (d, J=12.3 Hz, 1H), 4.63 (m,1H), 4.49 (dd, J=13.5, 1.8 Hz, 1H), 4.27 (d, J=13.5 Hz, 1H), 3.97 (d,J=12.6 Hz, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 1.50 (s, 3H), 1.43 (s, 3H);¹³C NMR δ194.8, 166.7, 163.9, 149.5, 131.2, 115.7, 111.6, 105.0, 99.8,98.5, 77.3, 75.5, 61.9, 56.0, 55.7, 48.7, 27.3, 26.2.

[0214] Anal. Calcd for C₁₉H₂₁NO₉: C, 56.02; H, 5.20; N, 3.44. Found: C,56.20; H, 5.34; N, 3.39.

[0215] Preparation of Ketone IVm

[0216] To a solution of 2c (0.718 g, 2.0 mmol) in THF (10 mL) were addedEt₃N (1.01 g, 10.0 mmol), DMAP (0.024 g, 0.2 mmol), and2,6-dimethoxylbenzoyl chloride (0.482 g, 2.4 mmol) at 0° C. under N₂.Upon stirring to the completion as judged by TLC (about 12 h), thereaction mixture was quenched with water, extracted with EtOAc, dried(Na₂SO₄), filtered, concentrated, and purified by flash chromatographyto give compound 2d (where R is —C(═O)C[2,6-(OMe)₂Ph]) as a white solid(1.02 g, 97%): mp 63-67° C.; [α]²⁰ _(D)=−74.9 (c 1.07, CHCl₃); IR (KBr)1800, 1698, 1598 cm⁻¹; ¹H NMR δ7.34 (t, J=8.4 Hz, 1H), 6.59 (d, J=8.4Hz, 2H), 4.31−3.78 (m, 7H), 3.82 (s, 6H). 1.60 (s, 3H), 1.41 (s, 3H),0.94 (s, 9H), 0.23 (s, 3H), 0.19 (s, 3H); ¹³C NMR δ165.3, 157.1, 150.3,131.5, 109.5, 103.8, 101.7, 76.9, 73.14, 73.1, 62.2, 56.1, 50.9, 28.4,26.4, 26.0, 18.3, −3.7, −5.1.

[0217] TBS ether 2d (where R is —C(═O)C[2,6-(OMe)₂Ph]) (0.64 g, 1.22mmol) was desilylated with Et₃N.3HF (0.99 g, 6.12 mmol) in a way similarto 2d (where R is Boc) to give the alcohol as a white solid (0.498 g,99%) (about 3 days): mp 75-78° C.; [α]²⁰ _(d)=−87.6 (c 1.02, CHCl₃); IR(KBr) 3447, 1799, 1694, 1597 cm⁻¹; ¹H NMR δ7.35 (t, J=8.4 Hz, 1H), 6.59(d, J=8.4 Hz, 2H), 4.35−4.13 (m, 5H), 4.00 (d, J=11.7 Hz, 1H), 3.82 (m,1H), 3.81 (s, 6H), 1.57 (s, 3H), 1.41 (s, 3H); ¹³C NMR δ165.5, 157.2,150.5, 131.7, 112.9, 109.9, 103.9, 101.8, 76.2, 73.0, 71.3, 62.3, 56.2,50.8, 28.2, 26.2.

[0218] The above alcohol (0.308 g, 0.753 mmol) was oxidized with PDC togive ketone IVm as a white solid (0.268 g, 87%); mp 72-73° C.; [α]²⁰_(D)=−60.6 (c, 1.12, CHCl₃); IR (KBr): 3481, 1805, 1758, 1698, 1597cm⁻¹; ¹H NMR δ7.34 (t, J=8.4 Hz, 1H), 6.57 (d, J=8.4 Hz, 2H), 4.79 (d,J=5.4 Hz, 1H), 4.74 (d, J=12.3 Hz, 1H), 4.62 (m, 1H), 4.48 (dd, J=13.5,2.1 Hz, 1H), 4.26 (d, J=13.5 Hz, 1H), 3.99 (d, J=12.3 Hz, 1H), 3.80 (s,6H), 1.50 (s, 3H), 1.43 (s, 3H); ¹³C NMR δ194.8, 157.3, 149.0, 143.8,132.0, 112.5, 111.5, 103.9, 99.6, 77.3, 75.5, 61.8, 56.2, 48.1, 27.3,26.2. Anal. Calcd for C₁₉H₂₁NO₉: C, 56.02; H, 5.20; N, 3.44. Found: C,55.96; H, 5.26; N, 3.41.

[0219] Preparation of Ketone IVn

[0220] To a solution of 2c (2.48 g, 6.91 mmol) in CH₃CN—H₂O (9/1, v/v)(21 mL) was added DDQ (0.153 g, 0.691 mmol). Upon stirring at rt for 6h, the reaction mixture was concentrated, redissolved in EtOAc, dried(Na₂SO₄), filtered, concentrated, and purified by flash chromatographyto give diol 2f as a pink solid (2.053 g, 93%): mp 210-213° C.; IR (KBr)3340, 1752 cm⁻¹; ¹H NMR (CD₃CN) δ5.78 (s, 1H), 3.94 (d, J=12.9 Hz, 1H),3.83 (m, 1H), 3.78−3.69 (m, 3H), 3.64 (d, J=10.5 Hz, 1H), 3.29−3.23 (m,3H), 0.87 (s, 9H), 0.15 (s, 3H), 0.13 (s, 3H); ¹³C NMR (CD₃CN) δ157.9,106.4, 73.1, 71.1, 70.1, 66.4, 49.7, 26.3, 19.0, −3.2, −5.1. Anal. Calcdfor C₁₃H₂₅NO₆Si: C, 48.88; H, 7.89; N, 4.38. Found: C, 48.79; H, 7.65;N, 4.45.

[0221] To a solution of 2f (0.638 g, 2.0 mmol) in CH₂Cl₂ (5 mL) wereadded TsOH ( 0.038 g, 0.2 mmol) and petanone (0.516 g, 6.0 mmol). Uponstirring at rt to the completion as judged by TLC (about 24 h), thereaction mixture was diluted with EtOAc, washed with water and brine,dried (Na₂SO₄), filtered, concentrated, and purified by flashchromatography to give compound 2g as a white solid (0.51 g, 66%): mp158.5-159.5° C.; [α]²⁰ _(D)=−84.1 (c 1.68, CHCl₃); IR (KBr) 3333, 1770cm⁻¹; ¹H NMR δ6.06 (s, 1H), 4.28−4.04 (m, 4H), 3.68 (d, J=6.0 Hz, 1H),3.67 (d, J=9.0 Hz, 1H), 3.40 (d, J=9.0 Hz, 1H), 1.82−1.66 (m, 2H), 1.62(q, J=7.5 Hz, 2H), 0.97 (t, J=7.5 Hz, 3H), 0.89 (t, J=7.5 Hz, 3H), 0.88(s, 9H), 0.19 (s, 3H), 0.10 (s, 3H); ¹³C NMR δ158.0, 113.6, 104.9, 76.8,73.8, 72.9, 62.3, 49.1, 30.5, 28.4, 26.0, 18.3, 8.93, 8.87, −3.7, −5.2.Anal. Calcd for C₁₈H₃₃NO₆Si: C, 55.79; H, 8.58; N, 3.61. Found: C,55.66; H, 8.49; N, 3.79.

[0222] Compound 2h was prepared in a way similar to 2d (where R is Boc):white solid (93%); mp 102-104° C.; [α]²⁰ _(D)=−59.1 (c 1.16, CHCl₃); IR(KBr) 1807, 1724 cm⁻¹; ¹H NMR δ4.30−4.18 (m, 3H), 4.08 (d, J=12.9 Hz,1H), 3.94 (d, J=10.5 Hz, 1H), 3.69 (d, J=10.5 Hz, 1H), 3.68 (d, J=6.6Hz, 1H), 1.82−1.65 (m, 2H), 1.62 (q, J=7.5 Hz, 2H), 1.52 (s, 9H), 0.98(t, J=7.5 Hz, 3H), 0.89 (t, J=7.5 Hz, 3H), 0.86 (s, 9H), 0.19 (s, 3H),0.12 (s, 3H); ¹³C NMR δ150.3, 148.9, 113.7, 101.1, 84.1, 76.7, 74.1,72.7, 62.7, 52.0, 30.5, 28.4, 28.2, 25.9, 18.2, 8.9, −3.7, −5.3. Anal.Calcd for C₂₃H₄₁NO₈Si: C, 56.65; H, 8.47; N, 2.87.

[0223] Found: C, 56.62; H, 8.24; N, 2.87.

[0224] TBS ether 2h (0.596 g, 1.224 mmol) was desilylated with Et₃N.3HF(0.986 g, 6.12 mmol) in a way similar to 2d (where R is Boc) to give thealcohol as a colorless oil (0.451 g, 99%) (about 4 days): [α]²⁰_(D)=−92.1 (c 0.70, CHCl₃); IR (KBr) 3478, 1817, 1728 cm⁻¹; ¹H NMRδ4.26−4.11 (m, 3H), 4.06 (d, J=10.8 Hz, 1H), 3.99 (d, J=13.2 Hz, 1H),3.84 (s, 1H, OH), 3.68 (d, J=6.6 Hz, 1H), 3.63 (d, J=10.8 Hz, 1H), 1.64(q, J=7.5 Hz, 2H), 1.54 (q, J=7.5 Hz, 2H), 1.42 (s, 9H), 0.86 (t, J=7.5Hz, 3H), 0.80 (t, J=7.2 Hz, 3H); ¹³C NMR δ150.5, 148.7, 113.6, 101.1,84.0, 75.8, 72.6, 70.9, 62.2, 51.5, 30.0, 28.5, 27.9, 8.6, 8.5. Anal.Calcd for C₁₇H₂₇NO₈: C, 54.68; H, 7.29; N, 3.75. Found: C, 54.48; H,7.18; N, 3.91.

[0225] The above alcohol (0.39 g, 1.05 mmol) was oxidized with PDC togive ketone IVn as a colorless oil (0.361 g, 93%): [α]²⁰ _(D)=−25.7 (c2.37, CHCl₃): IR (KBr) 3454 (hydrate), 1833, 1754, 1732 cm⁻¹; ¹H NMRδ4.73 (d, J=6.0 Hz, 1H), 4.63 (dd, J=6.0, 1.8 Hz, 1H), 4.51 (d, J=11.2Hz, 1H), 4.46 (dd, J=13.8, 1.8 Hz, 1H), 4.23 (d, J=13.8 Hz, 1H), 3.70(d, J=11.2 Hz, 1H), 1.70−1.59 (m, 4H), 1.53 (s, 9H), 0.94−0.87 (m, 6H);¹³C NMR δ194.9, 148.8, 148.4, 115.5, 98.7, 84.9, 76.8, 75.0, 61.7, 48.8,29.8, 29.1, 28.1, 8.7, 8.4. Anal. Calcd for C₁₇H₂₅NO₈: C, 54.98; H,6.79; N, 3.77. Found: C, 55.06; H, 6.91; N, 3.71.

[0226] HRMS Calcd for C₁₇H₂₆NO₈ (M⁺+1): 372.1658. Found: 372.1662

[0227] Preparation of Ketone IVo

[0228] A mixture of thiocarbonyldiimidazole (1.12 g, 6.3 mmol) and diol2f (1.826 g, 5.724 mmol) in toluene (30 mL) was heated at reflux for 1h. Upon cooling, the reaction mixture was washed with water, the brine,dried (Na₂SO₄), filtered, concentrated, and purified by flashchromatography to give 2i as a white solid (1.523 g, 74%): mp 219-222°C.; [α]²⁰ _(D)=−102.5 (c 0.49, CHCl₃); ¹H NMR δ5.95 (s, 1H), 5.02−4.90(m, 2H), 4.33 (s, 2H), 3.79 (d, J=6.0 Hz, 1H), 3.73 (d, J=9.6 Hz, 1H),3.25 (d, J=9.6 Hz, 1H), 0.90 (s, 9H), 0.24 (s, 3H), 0.17 (s, 3H); ¹³CNMR δ190.1, 156.9, 103.6, 82.2, 79.5, 71.4, 60.2, 48.6, 25.8, 18.3,−3.9, −5.1. Anal. Calcd for 6SSi: C, 46.52; H, 6.41; N, 3.87. Found: C,46.70; H, 6.39; N, 4.03.

[0229] Compound 2i (0.5 g, 1.385 mmol), Ph₃SnH (0.972 g, 2.77 mmol), andAIBN (0.014 g, 0.085 mmol) were dissolved in anhydrous toluene (35 mL).Upon stirring at reflux to the completion as judged by TLC, the reactionmixture was concentrated and purified by flash chromatography to give 2jas a white solid (0.457 g, 99%): mp 179-182° C.; [α]²⁰ _(D)=−95.5 (c1.17, CHCl₃); IR (KBr) 3295, 1767 cm⁻¹; ¹H NMR δ6.27 (s, 1H), 5.18 (s,1H), 5.00 (s, 1H), 4.31−4.25 (m, 2H), 4.16 (d, J=13.8 Hz, 1H), 4.01 (dd,J=5.4, 1.8 Hz, 1H), 3.69 (d, J=9.3 Hz, 1H), 3.60 (d, J=7.2 Hz, 1H), 3.39(d, J=9.3 Hz, 1H), 0.87 (s, 9H), 0.17 (s, 3H), 0.09 (s, 3H); ¹³C NMRδ158.0, 104.9, 94.8, 76.3, 74.4, 71.5, 61.6, 48.8, 25.9, 18.3, −3.8,−5.2. Anal. Calcd for C₁₄H₂₅NO₆Si: C, 50.73; H, 7.60; N, 4.23. Found: C,50.86; H, 7.56; N, 4.22.

[0230] Compound 2k was prepared in a way similar to 2d (where R is Boc):white solid (0.522 g, 88%); mp 119.0-120.5° C.; [α]²⁰ _(D)=−65.0 (c1.13, CHCl₃); IR (KBr) 1827, 1807, 1726 cm⁻¹; ¹H NMR δ5.20 (s, 1H), 5.03(s, 1H), 4.31−4.24 (m, 3H), 4.04 (m, 1H), 3.99 (d, J=10.8 Hz, 1H), 3.72(d, J=10.8 Hz, 1H), 3.63 (d, J=7.2 Hz, 1H), 1.54 (s, 9H), 0.88 (s, 9H),0.20 (s, 3H), 0.13 (s, 3H); ¹³C NMR δ150.2, 148.8, 101.1, 94.8, 84.2,76.0, 74.2, 71.8, 62.0, 51.7, 28.2, 25.9, 18.2, −3.9, −5.4. Anal. Calcdfor C₁₉H₃₅NO₈Si: C, 52.88; H, 7.71; N, 3.25. Found: C, 52.92; H, 7.60;N, 3.40.

[0231] TBS ether 2k (0.522 g, 1.21 mmol) was desilylated with Et₃N.3HF(0.975 g, 6.06 mmol) in a way similar to 2d (where R is Boc) to give thealcohol as a colorless oil (0.363 g, 94%) (about 4 days): [α]²⁰_(D)=−115.7 (c 1.28, CHCl₃); IR (KBr) 3468, 1812, 1726 cm⁻¹; ¹H NMRδ5.21 (s, 1H), 4.99 (s, 1H), 4.32 (dd, J=7.5, 5.4 Hz, 1H), 4.24 (dd,J=13.5, 2.0 Hz, 1H), 4.18 (d, J=13.5 Hz, 1H), 4.14 (d, J=10.8 Hz, 1H),4.04 (dd, J=5.7, 2.0 Hz, 1H), 3.72 (d, J=10.8 Hz, 1H), 3.65 (dd, J=7.5,7.2 Hz, 1H), 3.41 (d, J=7.2 Hz, 1H), 1.51 (s, 9H); ¹³C NMR δ150.6,148.9, 101.1, 95.0, 84.5, 75.7, 74.2, 69.5, 61.6, 51.3, 28.1. Anal.Calcd for C₁₃H₁₉NO₈: C, 49.21; H, 6.04; N, 4.41. Found: C, 49.26; 1,5.96; N, 4.54.

[0232] The above alcohol (0.309 g, 0.974 mmol) was oxidized with PDC togive ketone IVo as a colorless oil (0.30 g, 98%): [α]²⁰ _(D)=−35.6 (c1.22, CHCl₃); IR (KBr) 3453, 1821, 1757, 1729 cm⁻¹; ¹H NMR δ5.13 (s,1H), 4.99 (s, 1H), 4.83 (d,J=5.4 Hz, 1H), 4.52−4.42 (m, 3H), 4.26 (d,J=13.5 Hz, 1H), 3.67 (d, J=11.7 Hz, 1H), 1.49 (s, 9H); ¹³ C NMR δ193.6,148.7, 148.3, 98.7, 95.8, 84.9, 78.4, 74.6, 61.1, 48.4, 28.0. Anal.Calcd for C₁₃H₁₇NO₈: C, 49.52; H, 5.43; N, 4.44. Found: C, 49.37; H,5.60; N, 4.31. HRMS Calcd for C₁₃H₁₈NO₈(M⁺+1): 316.1032. Found:316.1040.

[0233] Preparation of Ketone IVp

[0234] A suspension of thiocarbonate 2i (0.565 g, 1.566 mmol) in1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine (0.911 g, 4.698 mmol) wasstirred under N₂ at 40° C. for 20 h. Upon cooling, the mixture waspurified by flash chromatography to give olefin 21 as a colorless oil(0.287 g, 64%): [α]²⁰ _(D)=+9.63 (c 1.6, CHCl₃); IR (KBr) 3281, 1763cm⁻¹; ¹H NMR δ6.53 (s, 1H), 5.77 (d, J=10.5 Hz, 1H), 5.65 (d, J=10.5 Hz,1H), 4.48 (dd, J=16.5, 1.2 Hz, 1H), 4.26 (s, 1H), 4.17 (dd, J=16.5, 1.2Hz, 1H), 3.64 (d, J=9.6 Hz, 1H), 3.40 (d, J=9.6 Hz, 1H), 0.88 (s, 9H),0.12 (s, 3H), 0.10 (s, 3H); ¹³C NMR δ158.5, 126.1, 125.5, 102.6, 67.5,63.0, 49.3, 25.8, 18.1, −3.7, −4.6.

[0235] Compound 2m was prepared in a way similar to 2d (where R is Boc)colorless oil (78%); [α]²⁰ _(D)=+19.0 (c 1.45, CHCl₃); IR (KBr) 1827,1806, 1726 cm⁻¹; ¹H NMR δ5.80−5.74 (m, 1H), 5.66−5.61 (m, 1H), 4.50−4.42(m, 1H), 4.29−4.26 (m, 1H), 4.25−4.17 (m, 1H), 3.91 (d, J=10.5 Hz, 1H),3.71 (d, J=10.5 Hz, 1H), 1.52 (s, 9H), 0.87 (s, 9H), 0.13 (s, 3H), 0.11(s, 3H); ¹³C NMR δ150.5, 149.1, 125.7, 125.4, 98.8, 83.9, 67.8, 63.6,52.2, 28.2, 25.8, 18.1, −3.6, −4.7.

[0236] A mixture 2m (0.303 g, 0.787 mmol) and 10% Pd—C (0.0303 g) inMeOH (10 mL) was stirred under H₂ for 24 h. Upon filtration, the mixturewas concentrated and purified by flash chromatography to give 2n as acolorless oil (0.301 g, 990): [α]²⁰ _(D)=−13.7 (c 1.31, CHCl₃); IR (KBr)1824, 1799, 1727 cm⁻¹; ¹H NMR δ3.90 (d, J=8.0 Hz, 1H), 3.93−3.86 (m,1H), 3.72−3.68 (m, 1H), 3.61−3.57 (m, 1H), 3.57 (d, J=8.0 Hz, 1H), (m,4H), 1.50 (s, 9H), 0.83 (s, 9H), 0.065 (s, 6H); ¹³C NMR δ8 150.9, 149.2,101.4, 83.7, 71.6, 63.3, 52.3, 28.1, 28.0, 25.7, 24.4, 17.9, −3.5, −5.0.HRMS Calcd. for C₁₈H₃₄NO₆Si (M⁺+1). 388.2155. Found: 388.2163.

[0237] TBS ether 2n (0.3 g, 0.775 mmol) was desilylated with Et₃N.3HF(0.625 g, 3.876 mmol) in a way similar to 2d (where R is Boc) to givethe alcohol as a colorless oil (0.187 g, 88%) (about 4 days): [α]²⁰_(D)=−71.2 (c 1.10, CHCl₃); IR (KBr) 3496, 1806, 1725 cm⁻¹; ¹H NMR δ4.11(d, J=8.1 Hz, 1H), 3.85 (td, J=8.4, 2.4 Hz, 1H), 3.70 (dd, J=8.4, 2.4Hz, 1H), 3.63 (d, J=8.1 Hz, 1H), 3.52 (m, 1H), 2.59 (s, 1H), 2.06 (m,1H), 1.82−1.71 (m, 3H), 1.50 (s, 9H); ¹³C NMR δ151.4, 149.1, 102.0,84.1, 69.1, 62.9, 51.6, 28.15, 28.1, 24.7. HRMS Calcd. for C₁₂H₂₀NO₆(M⁺+1): 274.1291. Found: 274.1291.

[0238] The above alcohol (0.18 g, 0.659 mmol) was oxidized with PDC togive ketone IVp as a colorless oil (0.16 g, 90%): [α]²⁰ _(D)=+15.1 (c1.24, CHCl₃); IR (KBr) 3475, 1827, 1736cm⁻¹; ¹H NMR δ4.47(d, J=11.1 Hz,1H),4.26(td, J=11.4, 3.6Hz, 1H), 3.89−3.83 (m, 1H), 3.49 (d, J=11.1 Hz,1H), 2.86−2.75 (m, 1H), 2.61−2.55 (m, 1H), 2.27−2.08 (m, 2H), 1.45 (s,9H); ¹³C NMR δ197.0, 149.1, 148.5, 99.0, 84.3, 62.7, 48.5, 35.8, 27.9,27.0. HRMS Calcd. for C₁₂H₁₈NO₆ (M⁺+1): 272.1134. Found: 272.1139.

Example 3

[0239] This example illustrates another method for synthesizingcompounds of Formula IV where the substituent on the nitrogen atom ispresent in the starting amine compound used.

[0240] A mixture of D-Glucose (30.0 g, 0.167 mol), p-toluidine (24.0 g,0.224 mol) and acetic acid (180 mg, 0.003 mol) in water (9 mL) wasstirred at 100° C. for 1 hour. Then 300 mL of ethanol was added. Thereaction mixture was put to freezer at −25° C. for 24 hours. The solidwas filtered and washed with ether-ethanol (3/2, 150 mL) to give theproduct (26.4 g, 59% yield). mp. 152-153 C. [α]²⁵=−23.0 (c 1.0,pyridine); ¹H NMR δ6.87 (d, J=8.4 Hz, 2H), 6.55 (d, J=8.4 Hz, 2H), 5.50(s, 1H), 4.89 (br, 1H), 4.45 (br, 2H), 3.85 (d, J=12.0 Hz, 1H),3.68−3.40 (m, 4H), 3.00 (d, J=12.0 Hz, 1H), 2.20 (s, 3H); ¹³C NMR 146.9,129.1, 124.2, 112.5, 98.2, 70.1, 69.3, 68.8, 63.4, 49.8, 20.2.

[0241] To a suspension of 1-p-toluidino-1-deoxy-D-fructose (19.37 g,0.072 mol) and trimethyl orthoformate (16 mL, 0.146 mol) in acetone (1L) at 0° C. was added H₂SO₄ (12 mL, 0.225 mol). The mixture was stirredat 0° C. for 2 hours, then quenched by NH₃.H₂O (˜60 mL). The salt wasfiltered, the filtration was concentrated and residue was dissolved indichloromethane, dried over Na₂SO₄, filtered and concentrated to about50 mL. To this solution was added 150 mL of refluxing hexane. Afterstanding at rt for 1 hour and 2 hours at −25° C., the solid was filteredand washed with cold hexane to give the product (19.44 g, 87% yield).mp. 39-41° C.; [α]²⁵=−138 (c 0.5, CHCl₃); ¹H NMR 7.01 (m, 2H), 6.71 (m,2H), 4.23 (m, 2H), 4.17 (dd, J=13.5, 2.4 Hz, 1H), 4.00 (d, J=13.5 Hz,1H), 3.61 (d, J=13.2 Hz, 1H), 3.59 (d, J=6.0 Hz, 1H), 3.21 (d, J=13.2Hz, 1H), 2.25 (s, 3H), 1.56 (s, 3H), 1.39 (s, 3H); ¹³C NMR 145.6, 130.0,128.7, 114.8, 109.4, 96.5, 77.4, 73.7, 72.1, 59.6, 50.8, 28.3, 26.4,20.6; IR 3420 cm⁻¹.

[0242] To a solution of the above alcohol (7.72 g, 0.025 mol) andtriethyl amine (10 mL, 0.072 mol) in dichloromethane at 0° C. was addeddropwise phosgene in toluene (16.5 mL, 0.031 mol) over 30 min. Themixture was then stirred at 0° C. for 6 hours, quenched with 1 M NaOH(60 mL), and stirred for 5 min. The layers were separated, and theaqueous layer was extracted with dichloromethane. The combined organicphase was washed with 1 M HCl, saturated NaHCO₃, brine, dried,concentrated, dissolved in 100 mL of methanol. To this solution wasadded solid K₂CO₃ (3.45 g, 0.025 mol) and stirred at rt for 30 min. Thesolvent was removed under reduced pressure, the residue was dissolvedCH₂Cl₂, washed with water, dried, concentrated to 30 mL. Then refluxinghexane (90 mL) was added. After standing at rt for 1 hour and 1 hour at−25° C., the solid was filtered and washed with cold hexane to give theproduct (7.0 g, 84% yield). mp: 170-172° C.; [α]²⁵=−93.0 (c 0.43,CHCl₃); ¹H NMR 7.37 (m, 2H), 7.20 (m, 2H), 4.3 (m, 4H), 4.2 (d, J=13.5Hz, 1H), 3,78 (d, J=13.5 Hz, 1H), 3.10 (br, 1H), 2.32 (s, 3H), 1.57 (s,3H), 1.40 (s, 3H); ¹³C NMR 152.7, 135.6, 134.3, 129.3, 118.2, 118.2,110.0, 101.0, 76.6, 73.3, 71.6, 62.0, 53.4, 28.3,26.3, 21.1; IR 3420cm⁻¹.

[0243] To a solution of the above alcohol (6.70 g, 0.02 mol) in CH₂Cl₂(100 mL) was added freshly grounded 3 Å molecular sieves (18.0 g), PDC(11.28 g, 0.03 mol) and 3 drops oof acetic acid. After stirred at rtovernight, the mixture was passed through a pad of celite, washed withether, then passed through a short column of silica gel, washed withether. The ether was concentrated and the residue was dissolved in 15 mLof CH₂Cl₂. Then refluxing hexane (60 mL) was added. After standing at rtfor 3 hours and 2 hours in freezer, the solid part was filtered to give4.20 g of the product. The filtrate was concentrated and purified onsilica gel with hexane-ethyl acetate (1:1) to give additional 0.6 g ofthe product. The yield was 72%. mp. 149-150° C.; [α]²⁵=−41.4 (c 0.34,CHCl₃); ¹H NMR 7.39 (m, 2H), 7.18 (m, 2H), 4.87 (d, J=5.7 Hz, 1H), 4.73(d, J=10.8 Hz, 1H), 4.63 (m, 2H), 4.25 (dd, J=14.4, 1.5 Hz, 1H), 3.74(d, J=10.8 Hz, 1H), 2.33 (s, 3H), 1.48 (s, 3H), 1.43 (s, 3H); ¹³C NMR195.0, 151.7, 134.8, 134.6, 129.7, 118.8, 111.1, 99.2, 77.6, 75.6, 61.0,50.0, 27.3, 26.1, 21.0; IR 1772 cm⁻¹.

Example 4

[0244] This example illustrates the ability of Compounds of Formula I toasymmetrically epoxidize a variety of olefins.

[0245] Representative Asymmetric Epoxidation Procedure

[0246] To a solution of cis-β-methyl styrene (0.059 g, 0.5 mmol) andketone IVd (0.026 g, 0.075 mmol) in DME-DMM (3:1, v/v) (7.5 mL) wereadded buffer (0.2 M K₂CO₃—AcOH in 4×10⁻⁴ M aqueous EDTA, buffer pH=8.0)(5 mL) and Bu₄NHSO₄ (0.0075 g, 0.02 mmol) with stirring. After themixture was cooled to about −10° C. (bath temperature) via a NaCl-icebath, a solution of Oxone® (0.212 M in 4×10⁻⁴ M aqueous EDTA, 4.2 mL)(0.548 g, 0.89 mmol) and K₂CO₃ (0.479 M in 4×10⁻⁴ M aqueous EDTA, 4.2mL) (0.278 g, 2.01 mmol) were added dropwise separately over a period of3.5 h via a syringe pump. The reaction was then quenched with theaddition of pentane and extracted with pentane. The combined organiclayers were washed with brine, dried (Na₂SO₄), filtered, concentrated,and purified by flash chromatography (the silica gel was buffered with1% Et₃N in pentane; pentane-ether (1/0 to 50/1 was used as eluent) togive cis-β-methylstyrene oxide as a colorless liquid (0.58 g, 87% yield,91% ee).

[0247] Some of the epoxidation studies using ketones of Formulas IV andXII as catalysts are shown in Tables 2-6 below. TABLE 2 AsymmetricEpoxidation of Olefins Catalyzed by Ketones of Formula XII EntrySubstrate Ketone (eq.) Conv. (%) Yield (%) ee (%)

XIIa (0.05) 86 72 XIIb (0.05) 99 83 XIIc (0.05) 99 82 XIIe (0.05) 99 88

XIIa (0.05) 27 98 XIIb (0.05) 71 97 XIIc (0.05) 95 98

XIIc (0.05) 85 87 XIIe (0.05) 89 88

XIIb (0.05) 84 69 88 XIIc (0.05) 82 61 88 XIIe (0.05) 99 93

XIIe (0.05) 77 92

XIIb (0.05) 99 96 XIIc (0.02) 94 89 XIIe (0.02) 74 88

XIIb (0.05) 89 85 92 XIIc (0.02) 73 92 XIIe (0.05) 93 91

[0248] TABLE 3 Asymmetric Epoxidation of cis-olefins Catalyzed by KetoneIVd^(a) Entry Substrate Yield (%)^(b) ee (%) Configuration  1^(c)

87 91^(i) (−)-(1R,2S)^(n,15a,b)  2^(c)

76^(h) 92^(i) (1R,2S)^(o,15c)  3^(c)

79^(h) 88^(i) (1R,2S)^(o)  4^(c)

58^(h) 93^(i) ND  5^(c)

74^(h) 92^(i) (1R,2S)^(o)  6^(d)

63^(h) 90^(i) (1R,2S)^(o)  7^(c)

91 92^(i) (−)-(1R,2S)^(p)  8^(e)

88 83^(k) (−)-(1R,2S)^(n,15d)  9^(c)

88 84^(k) (+)-(1R,2S)^(n,15d,10d) 10^(e)

77 91^(l) (−)-(5R,6S)^(n,15e,f) 11^(f)

61 91^(m) (+)-(3R,4R)^(n,15g,h) 12^(g)

82 91^(m) (−)-(2S,3R)^(q,10a,d) 13^(d)

77 87^(m) (−)-(2S,3R)^(q) 14^(d)

47 96^(i) (+) 15^(d)

61 97^(i) (+)^(15i) 16^(d)

88 94^(i) (+)

[0249] TABLE 4 Asymmetric Epoxidation of Terminal Olefins Catalyzed byKetone IVd^(a) entry substrate yield (%)^(b) ee (%) configuration.^(i) 1^(c)

92 81^(f) (−)-(R)^(17a)  2^(d)

61 81^(f) (−)-(R)^(17a)  3^(d)

74 83^(f) (−)-(R)^(17a)  4^(d)

90 85^(f) (−)-(R)^(17a)  5^(d)

87 82^(f) (−)-^(17b)  6^(d)

93 81^(f) (−)^(17c)  7^(d)

94 81^(f) (−)-(R)^(17d)  8^(e)

88 74^(f) (−)⁴  9^(c)

86 84^(g) (−)-(R)^(17e) 10^(d)

93 71^(f) ND^(17f,g) 11^(d)

88 30^(h) (+)-(S)^(17a) 12^(d)

87 58^(f) (+)^(17h)

[0250] TABLE 5 Asymmetric epoxidation of trans- and trisubstitutedolefins catalyzed by ketone IVd^(a) Entry Substrate Yield (%)^(b) ee (%)Configuration 1^(c)

65 94^(e) (+)-(R,R)^(g,18,7c) 2^(d)

91 77^(f) (+)-(R,R)^(g,15a,7c) 3^(d)

78 95^(f) (+)^(7c) 4^(d)

68 42^(f) (−)-(S,S)^(g,7c) 5^(d)

55 80^(e) (+)^(7c)

[0251] TABLE 6 Asymmetric Epoxidation of Olefins Catalyzed by KetonesIVa-IVp and 17^(a)

entry ketone conv.(ee)^(b) conv.(ee)^(c) conv.(ee)^(d) conv.(ee)^(e)conv.(ee)  1 IVa 100 (62) 100 (59) 100 (76) 100 (79) 100 (55) (R,R)  2IVb 100 (72) 100 (79) 100 (79) 100 (92) 100 (40) (R,R)  3 IVc 100 (65)100 (70) 100 (81) 100 (90) 100 (59) (R,R)  4 IVd 100 (79) 100 (87) 100(77) 100 (94) 100 (23) (S,S)  5 IVe 100 (75) 100 (89) 100 (73) 100 (94)100 (46) (S,S)  6 IVf 88 (61) 100 (59)  97 (72) 100 (69) 100 (65) (R,R) 7 IVg 87 (73) 100 (87) 100 (73) 100 (95) 100 (44) (S,S)  8 IVh 99 (70)100 (78) 100 (75) 100 (89) 100 (51) (R,R)  9 IVi 94 (73) 100 (86)  85(73) 100 (95) 100 (18) (S,S) 10 IVj 100 (73) 100 (87) 100 (74) 100 (93)100 (14) (S,S) 11 IVk 100 (66)  97 (78) 100 (71) 100 (90) 100 (12) (R,R)12 IVl 100 (63) 100 (74) 100 (69) 100 (88) 100 (6) (R,R) 13 IVm 100 (52)100 (47) 100 (70) 100 (54) 100 (69) (R,R) 14 IVn 100 (77) 100 (80) 100(75) 100 (91) 100 (23) (S,S) 15 IVo 100 (69) 100 (79) 100 (73) 100 (93)100 (29) (S,S) l6^(f) IVp 100 (47) 100 (39) 100 (61) 100 (78) 100 (2)(R,R) 17^(g) 17  49 (<1)  91 (16)^(h)  83 (32)  64 (3)  66 (64) (R,R)^(a)All reactions were carried out with olefin (1 equiv), ketone (0.15equiv), Bu₄NHSO₄ (0.05 equiv), Oxone (1.6 equiv), and K₂CO₃ (4.2 equiv)in DME/DMM (3:1, v/v) and buffer (0.2 M K₂CO₃-AcOH, pH 8.0) at 0° C..The reactions were stopped after 3.5 h. Enantioselectivity wasdetermined by chiral GC (Chiraldex G-TA). Compound 17 is of the formula:

^(b)The epoxide has the (R) configuration. ^(c)The epoxide has the(1R,2S) configuration unless otherwise noted. ^(d)The epoxide has the(R,R) configuration. ^(e)The epoxide has the (R) configuration. ^(f)0.3equiv ketone used. ^(g)1.0 equiv ketone used. ^(h)The epoxide has the(1S,2R) configuration.

[0252] Representative physical characteristics of the epoxidationproducts are shown below:

[0253] (1R,2S)-cis-β-Methylstyrene oxide (Table 3, entry 1). Colorlessoil; [α]²⁰ _(D)=−45.5 (c 0.67, CHCl₃).

[0254] (1R,2S)-1-(4-Methylphenyl)-1-propene oxide (Table 3, entry 2).Colorless oil; ¹H NMR δ7.16 (m, 4H), 4.04 (d, J=4.2 Hz, 1H), 3.29−3.26(m, 1H), 2.40 (s, 3H), 1.14 (D, J=5.1 Hz, 3H); ¹³C NMR δ128.8, 126.6,57.7, 55.3, 21.4, 12.7.

[0255] (1R,2S)-1-(3-Methylphenyl)-1-propene oxide (Table 3, entry 3).Colorless oil; ¹H NMR δ7.26−7.09 (m, 4H), 4.04 (d, J=4.2 Hz, 1H),3.37−3.30 (m, 1H), 2.37 (s, 3H), 1.10 (D, J=5.7 Hz, 3H); ¹³C NMR δ137.7,128.3, 128.0, 127.3, 123.7, 57.7, 55.3, 21.6, 12.8. HRMS Calcd. forC₁₀H₁₂O: 148.0888. Found: 148.0888.

[0256] (1R,2S)-1-(3,5-Dimethylphenyl)-1-propene oxide (Table 3, entry4). Colorless oil; ¹H NMR δ6.95−6.85 (m, 3H), 4.00 (d, J=4.2 Hz, 1H),3.32 (qd, J=5.7, 4.2, 1H), 2.32 (s, 6H), 1.10 (d, J=5.7 Hz, 3H); ¹³C NMRδ129.2, 124.4, 57.7, 55.2, 21.5, 12.8. HRMS Calcd. for C₁₁H₁₄O:162.1045. Found: 162.1042.

[0257] (1R,2S)-1-(4-Fluorophenyl)-1-propene oxide (Table 3, entry 5).Colorless oil; ¹H NMR δ7.30−7.19 (m, 2H), 7.09−6.98 (m, 2H), 4.03 (d,J=4.2 Hz, 1H), 3.33 (qd, J=5.1, 4.2 Hz, 1H), 1.07 (d, J=5.1 Hz, 3H); ¹³CNMR δ128.3, 128.2, 115.2, 115.0, 57.2, 55.3, 12.7. Anal. Calcd C₉H₉FO:C, 71.04; H, 5.96. Found: C, 71.21; H, 5.90.

[0258] (1R,2S)-1-(4-Trifluoromethylphenyl)-1-propene oxide (Table 3,entry 6). Colorless oil; ¹H NMR δ7.62 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.1Hz, 2H), 4.10 (d, J=4.2 Hz, 1H), 3.39 (m, 1H), 1.08 (d, J=5.4 Hz, 3H);¹³C NMR δ127.0, 125.1, 57.2, 55.4, 12.7. Anal. Calcd C₁₀H₉F₃: C, 59.41;H, 4.49. Found: C, 59.19; H, 4.65.

[0259] (1R,2S)-1-(2-Naphthyl)-1-propene oxide (Table 3, entry 7). Whitesolid; [α]²⁰ _(D)=−13.5 (c 1.31, CHCl₃); IR (KBr) 3051, 1511, 1341cm⁻¹;¹H NMR δ7.86−7.77 (m,4H), 7.50−7.44 (m, 3H), 4.23 (d, J=4.5 Hz, 1H),3.43 (qd, J=5.4, 4.5 Hz, 1H), 1.12 (d, J=5.4 Hz, 3H); ¹³C NMR δ133.1,132.9, 127.9, 127.8, 126.3, 125.9, 125.6, 124.6, 57.9, 55.6, 12.8. Anal.Calcd for C₁₃H₁₂O: C, 84.75; H, 6.57. Found: C, 84.60; H, 6.41.

[0260] (1R,2S)-Indene oxide (Table 3, entry 8). Colorless oil; [α]²⁰_(D)=−38.3 (c 1.2, CHCl₃).

[0261] (1R,2S)-3,4-Dihydronaphthalene oxide (Table 3, entry 9).Colorless oil; [α]²⁰ _(D)=+133.2 (c 1.57, CHCl₃).

[0262] (5R,6S)-5,6-Epoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene (Table3, entry 10). Colorless oil; [α]²⁰ _(D)=−23.4 (c 0.82, CHCl₃).

[0263] (3R,4R)-6-Cyano-3,4-epoxy-2,2-dimethylchromene (Table 3, entry11). White solid; [α]²⁰ _(D)=+62.7 (c 0.71, CHCl₃).

[0264] (2S,3R)-2-Methyl-3-(phenylethynyl)oxirane (Table 3, entry 12).Colorless oil; [α]²⁰ _(D)=−33.0 (c 0.98, CHCl₃).

[0265] (2S,3R)-2-Methyl-3-(1-octynyl)oxirane (Table 3. entry 13).Colorless oil; [α]²⁰ _(D)=−31.4 (c 0.29, CHCl₃); IR (KBr) 2215, 1347cm⁻¹; ¹H NMR δ3.45 (dt, J=3.9, 1.8 Hz, 1H), 3.16 (qd, J=5.1, 3.9 Hz,1H), 2.70 (td, J=7.2, 1.8 Hz, 2H), 1.63−1.25 (m, 8H), 1.45 (d, J=5.1 Hz,3H), 0.93 (t, J=6.9 Hz, 3H); ¹³C NMR δ100.1, 86.8, 54.1, 46.1, 31.5,30.1, 28.6, 22.7, 19.0, 14.9, 14.3. Anal. Calcd for C₁₁H₁₈O: C, 79.46;H, 10.91. Found: C, 79.28; H, 10.95.

[0266] (+)-3,3-Ethylenedioxycyclopentene oxide (Table 3, entry 14).Colorless oil; [α]²⁰ _(D)=+12.7 (c 0.132, CHCl₃); IR (KBr) 1347, 1130cm⁻¹; ¹H NMR δ4.10−3.85 (m, 4H), 3.51 (m, 1H), 3.25 (d, J=3 Hz, 1H),2.10 (m, 1H), 1.85−1.55 (m, 3H); ¹³C NMR δ114.8, 65.4, 65.0, 55.9, 55.7,29.5, 25.2. Anal. Calcd for C₇H₁₀O₃: C, 59.14; H, 7.09.

[0267] Found: C, 59.32; H, 7.18.

[0268] (+)-3,3-Ethylenedioxycyclohexene oxide (Table 3, entry 15).Colorless oil; [α]²⁰ _(D)=+9.7 (c 2.3, hexane).

[0269] (+)-3,3-Ethylenedioxycycloheptene oxide (Table 3, entry 16).Colorless oil; [α]²⁰ _(D)=+6.5 (c 0.71, CHCl₃); IR (KBr) 1147, 1087,1061 cm⁻¹; ¹H NMR δ4.10−3.86(m, 4H), 3.09 (td, J=5.3, 1.2 Hz, 1H), 2.95(dd, J=4.5, 1.2 Hz, 1H), 2.28−2.21 (m, 1H), 1.95−1.43 (m, 6H), 1.30−1.21(m, 1H); ¹³C NMR δ110.9, 65.1, 64.9, 59.4, 54.3, 34.9, 28.0, 23.7, 22.9.Anal. Calcd for C₉H₁₄O₃: C, 63.51; H, 8.29. Found: C, 63.65; H, 8.50.

[0270] (R)-(−)-Styrene oxide (Table 4, entry 1). Colorless oil; [α]²⁰_(D)=−19.2 (c 1.34, CHCl₃).

[0271] (R)-(−)-2-Chlorostyrene oxide (Table 4, entry 2). Colorless oil;[α]²⁰ _(D)=−49.7 (c 0.7, CHCl₃).

[0272] (R)-(−)-3-Chlorostyrene oxide (Table 4, entry 3). Colorless oil;[α]²⁰ _(D)=−10.3 (c 1.04, CHCl₃).

[0273] (R)-(−)-4-Chlorostyrene oxide (Table 4, entry 4). Colorless oil;[α]²⁰ _(D)=−21.8 (c 0.83, CHCl₃).

[0274] (R)-(−)-2-Fluorostyrene oxide (Table 4, entry 5). Colorless oil;[α]²⁰ _(D)=−13.2 (c 0.92, hexane)

[0275] (R)-(−)-3-Fluorostyrene oxide (Table 4, entry 6). Colorless oil;[α]²⁰ _(D)=−3.24 (c 1.27, hexane)

[0276] (R)-(−)-4-Fluorostyrene oxide (Table 4, entry 7). Colorless oil;[α]²⁰ _(D)=−14.0 (c 1.13, CHCl₃).

[0277] (−)-3-Nitrostyrene oxide (Table 4 entry 8). Colorless oil; [α]²⁰_(D)=−3.7 (c 0.46, CHCl₃).

[0278] (R)-(−)-2-Naphthyloxirane (Table 4, entry 9). White solid; [α]²⁰_(D)=−11.4 (c 0.67, CHCl₃).

[0279] Cyclohexyloxirane (Table 4, entry 10). Colorless oil.

[0280] (S)-(+)-α-Methylstyrene oxide (Table 4, entry 11). Colorless oil;[α]²⁰ _(D)=+2.78 (c 1.1, CHCl₃).

[0281] (+)-α-Isopropylstyrene oxide (Table 4, entry 12). Colorless oil;[α]²⁰ _(D)=+23.2 (c 0.6, hexane); ¹H NMR δ7.44−7.30 (m, 5H), 3.05 (d,J=5.1 Hz, 1H), 2.77 (d, J=5.1 Hz, 1H), 2.21−2.07 (m, 1H), 1.02 (d, J=6.9Hz, 3H), 1.00 (d, J=6.9 Hz, 3H); ¹³C NMR δ139.4, 128.0, 127.4, 127.3,64.7, 53.4, 33.4, 18.8, 18.1.

[0282] As shown in Tables 2-6, surprising and unexpectedly it was foundthat ketones of Formula IV gave very high enantioselectivity for theepoxidation of cis- and terminal olefins. In addition, high conversionsof olefins to epoxides were obtained with compounds of Formula XII evenwhen only 2-5 mole % of the ketone (i.e., Compound of Formula XII) wasused as a catalyst (see for example, Table 2).

[0283] The foregoing discussion of the invention has been presented forpurposes of illustration and description. The foregoing is not intendedto limit the invention to the form or forms disclosed herein. Althoughthe description of the invention has included description of one or moreembodiments and certain variations and modifications, other variationsand modifications are within the scope of the invention, e.g., as may bewithin the skill and knowledge of those in the art, after understandingthe present disclosure. It is intended to obtain rights which includealternative embodiments to the extent permitted, including alternate,interchangeable and/or equivalent structures, functions, ranges or stepsto those claimed, whether or not such alternate, interchangeable and/orequivalent structures, functions, ranges or steps are disclosed herein,and without intending to publicly dedicate any patentable subjectmatter. All references cited herein are incorporated by reference intheir entirety.

What is claimed is:
 1. A compound of the formula:

wherein one of R¹and R² is —OR^(a) and the other is -alkylene-OR^(b),where each of R^(a) and R^(b) is independently a non-ring forminghydroxy protecting group, or R¹ and R² together with the carbon atoms towhich they are attached to form an optionally substituted heterocyclyl;and each of R³ and R⁴ is independently hydrogen or —OR^(c), where R^(c)is a non-ring forming hydroxy protecting group, or R³ and R⁴ togetherwith the carbon atoms to which they are attached to form an optionallysubstituted heterocyclyl, provided at least one of R¹ and R² togetherwith the carbon atoms to which they are attached to or R³ and R⁴together with the carbon atoms to which they are attached to form anoptionally substituted nitrogen atom containing heterocyclyl.
 2. Thecompound according to claim 1, wherein the relative stereochemistry ofR³ and R⁴ is a cis-configuration.
 3. The compound according to claim 2,wherein said optionally substituted heterocyclyl is an optionallysubstituted 5-membered heterocyclyl ring.
 4. The compound according toclaim 2, wherein R¹ and R² together with the carbon atoms to which theyare attached to form an optionally substituted nitrogen atom containingheterocyclyl.
 5. The compound according to claim 4 of the formula:

or a stereoisomer thereof, wherein R³ and R⁴ are those defined in claim1; one of X¹ and X² is O and the other is NR⁷, where R⁷ is selected fromthe group consisting of hydrogen, alkyl, aryl, —(R⁸)_(n)—C(═O)—R⁹, andother nitrogen protecting group, where n is 0 or 1, R⁸ is alkylene, andR⁹ is hydroxy, alkyl, alkoxy, aryl, aryloxy and —NR^(a)R^(b), whereR^(a) and R^(b) is independently hydrogen or alkyl; and each of R⁵ andR⁶ is independently selected from the group consisting of hydrogen, andalkyl.
 6. The compound according to claim 5, wherein R³ and R⁴ togetherwith the carbon atoms to which they are attached to form an optionallysubstituted heterocyclyl.
 7. The compound according to claim 6 of theformula:

or a stereoisomer thereof, wherein R⁷ is that defined in claim 5; andeach of R¹⁰ and R¹¹ is independently selected from the group consistingof hydrogen, alkyl, aralkyl and aryl.
 8. The compound according to claim2, wherein R³ and R⁴ together with the carbon atoms to which they areattached to form an optionally substituted nitrogen atom containingheterocyclyl.
 9. The compound according to claim 8 of the formula:

wherein R¹ and R² are those defined in claim 1; and one of X¹ and X² isO and the other is NR⁷, where R⁷ is selected from the group consistingof hydrogen, alkyl, aryl, —(R⁸)_(n)—C(═O)—R⁹, and other nitrogenprotecting group, where n is 0 or 1, R⁸ is alkylene, and R⁹ is hydroxy,alkyl, alkoxy, aryl, aryloxy and —NR^(a)R^(b), where R^(a) and R^(b) isindependently hydrogen or alkyl.
 10. The compound according to claim 9,wherein R¹ and R² together with the carbon atoms to which they areattached to form an optionally substituted heterocyclyl.
 11. Thecompound according to claim 10 of the formula:

where R⁷ is that defined in claim 9; and each of R¹⁰ and R¹¹ isindependently selected from the group consisting of hydrogen, alkyl,aralkyl and aryl.
 12. A method for producing a spiro-bicyclic compoundof the formula:

wherein each of R³ and R⁴ is independently hydrogen or —OR^(c), whereR^(c) is a non-ring forming hydroxy protecting group, or R³ and R⁴together with the carbon atoms to which they are attached to form anoptionally substituted heterocyclyl; and R⁷ is selected from the groupconsisting of hydrogen, alkyl, aryl, —R⁸)_(n)—C(═O)—R⁹, and othernitrogen protecting group, where n is 0 or 1, R⁸ is alkylene, and R⁹ ishydroxy, alkyl, alkoxy, aryl, aryloxy and —NR^(a)R^(b), where R^(a) andR^(b) is independently hydrogen or alkyl; said method comprising: (a)contacting a carbohydrate with an amine under condition sufficient toproduce an amino tetrahydroxy carbohydrate; (b) protecting two hydroxygroups by contacting the amino tetrahydroxy carbohydrate with a hydroxyprotecting group under conditions sufficient to produce adihydroxy-protected amino dihydroxy carbohydrate; (c) forming aheterocyclic moiety by contacting the dihydroxy-protected aminodihydroxy carbohydrate with an activated carbonate under conditionssufficient to produce a hydroxy spiro-bicyclic compound; and (d)oxidizing the hydroxy group contacting the hydroxy spiro-bicycliccompound with an oxidizing agent under conditions sufficient to producethe spiro-bicyclic compound of Formula IA.
 13. The method of claim 12,wherein the spiro-bicyclic compound is enantiomerically enriched chiralcompound.
 14. The method of claim 13, wherein the carbohydrate isglucose.
 15. The method of claim 14, wherein the carbohydrate isD-glucose.
 16. The method of claim 14, wherein the enantiomericallyenriched spiro-bicyclic compound is of the formula:

or stereoisomers thereof, where R³, R⁴ and R⁷ are those defined in claim12.
 17. The method of claim 16, wherein the enantiomerically enrichedspiro-bicyclic compound is of the formula:

or a stereoisomer thereof, wherein R⁷ is that defined in claim 12; andeach of R¹⁰ and R¹² is independently selected from the group consistingof hydrogen, alkyl, aralkyl and aryl.
 18. The method of claim 12,wherein the activated carbonate is selected from the group consisting ofphosgene, triphosgene and a haloformate.
 19. The method of claim 12,wherein the amine is diaralkyl amine.
 20. The method of claim 19 furthercomprising removing aralkyl groups from the amino nitrogen by contactingthe dihydroxy-protected amino dihydroxy carbohydrate with hydrogen inthe presence of a hydrogenation catalyst under conditions sufficient toproduce a dihydroxy-protected free-amino carbohydrate prior to saidheterocyclic moiety forming step (c).
 21. A method for producing afused-bicyclic compound of the formula:

wherein R¹³ and R¹⁴ are hydroxy protecting groups or R¹³ and R¹⁴together with the carbon atoms to which they are attached to form anoptionally substituted heterocyclyl; and R¹⁵ is tosyl, hydrogen, alkyl,aryl, —R⁸)_(n)—C(═O)—R⁹, or other nitrogen protecting group, where n is0 or 1, R⁸ is alkylene, and R⁹ is hydroxy, alkyl, alkoxy, aryl, aryloxyand —NR^(a)R^(b), where R^(a) and R^(b) is independently hydrogen oralkyl; said method comprising (a) contacting a trihydroxy-protectedolefin compound of the formula:

where R¹³ and R1⁴ are hydroxy protecting groups or R¹³ and R¹⁴ togetherwith the carbon atoms to which they are attached to form an optionallysubstituted heterocyclyl; and R¹² is a hydroxy protecting group, with ahydroxy aminating agent under conditions sufficient to produce an aminohydroxy compound of the formula:

where R¹², R¹³, R¹⁴ and R¹⁵ are those defined above; (b) forming aheterocyclic moiety by contacting the amino hydroxy compound with anactivated carbonate under conditions sufficient to produce a fusedbicyclic compound of the formula:

where R¹², R¹³, R¹⁴ and R¹⁵ are those defined above; (c) selectivelyremoving the R¹² hydroxy protecting group by contacting the fusedbicyclic compound with a hydroxy protecting group removing agent underconditions sufficient to produce a monohydroxy fused bicyclic compoundof the formula:

where R¹³, R¹⁴ and R¹⁵ are those defined above; and (d) oxidizing thefree hydroxy group by contacting the monohydroxy fused bicyclic compoundwith an oxidizing agent under conditions sufficient to produce thefused-bicyclic compound of Formula IB.
 22. The method of claim 21,wherein the hydroxy aminating agent comprises chloramine-T trihydrateand K₂OsO₆H₄.
 23. The method of claim 22, wherein R¹⁵ of compound ofFormula ID is tosyl.
 24. The method of claim 23 further comprisingconverting R¹⁵ of compound of Formula ID to hydrogen, alkyl, aryl,—(R⁸)_(n)—C(═O)—R⁹, or other nitrogen protecting group, prior to saidheterocyclic moiety forming step (b), said converting step comprising:(i) removing the tosyl group of compound of Formula ID by contacting thecompound of Formula ID with a tosyl removing agent under conditionssufficient to provide a compound of Formula ID comprising a free aminegroup, where R¹⁵ is hydrogen; and (ii) optionally substituting the freeamine group by contacting the compound of Formula ID comprising a freeamine group with a compound of the formula R⁷—X under conditionssufficient to produce a compound of Formula ID, wherein R⁷ and R¹⁵ areidentical and is selected from the group consisting of alkyl, aryl,—(R⁸)_(n)—C(═O)—R⁹, or other nitrogen protecting group, where n, R⁸ andR⁹ are those defined in claim 21; and X is a leaving group.
 25. Themethod of claim 22, wherein R¹⁵ of compound of Formula IB is tosyl. 26.The method of claim 25 further comprising converting R¹⁵ of compound ofFormula IB to hydrogen, alkyl, aryl, —(R⁸)_(n)—C(═O)—R⁹, or othernitrogen protecting group, after said oxidizing step (d), saidconverting step comprising: (i) removing the tosyl group of compound ofFormula IB by contacting the compound of Formula IB with a tosylremoving agent under conditions sufficient to provide a compound ofFormula IB comprising a free amine group, where R¹⁵ is hydrogen; and(ii) optionally substituting the free amine group by contacting thecompound of Formula IB comprising a free amine group with a compound ofthe formula R⁷—X under conditions sufficient to produce a compound ofFormula IB, wherein R⁷ and R¹⁵ are identical and is selected from thegroup consisting of alkyl aryl, —(R⁸)_(n)—C(═O)—R⁹, or other nitrogenprotecting group, where n, R⁸ and R⁹ are those defined in claim 21; andX is a leaving group.
 27. The method of claim 21, wherein the activatedcarbonate is selected from the group consisting of phosgene,triphosgene, and a haloformate.
 28. The method of claim 21, wherein thetrihydroxy-protected olefin compound is produced from a carbohydrate.29. The method of claim 28, wherein the trihydroxy-protected olefincompound producing step comprises: (i) selectively protecting hydroxygroups of the carbohydrate with at least two different hydroxyprotecting groups by contacting the carbohydrate with a first hydroxyprotecting agent under conditions sufficient to produce a firstcarbohydrate comprising a first hydroxy protecting group and contactingthe first carbohydrate with a second hydroxy protecting agent underconditions sufficient to produce a second carbohydrate comprising afirst and a second hydroxy protecting groups, wherein the first and thesecond hydroxy protecting groups can be selectively removed; (ii)removing at least a portion of the first hydroxy protecting group bycontacting the second carbohydrate with a first hydroxy protecting groupremoving agent under conditions sufficient to produce a di-free hydroxycarbohydrate; and (iii) forming an olefinic bond by contacting thedi-free hydroxy carbohydrate with a dihydroxy eliminating agent underconditions sufficient to produce the trihydroxy-protected olefincompound.
 30. A method for producing an epoxide from an olefincomprising admixing a ketone, an olefin, and an oxidizing agent underconditions sufficient to produce the epoxide, where in the ketone is ofthe formula:

wherein one of R¹ and R² is —OR^(a) and the other is -alkylene-OR^(b),where each of R^(a) and R^(b) is independently a non-ring forminghydroxy protecting group, or R¹ and R² together with the carbon atoms towhich they are attached to form an optionally substituted heterocyclyl;and each of R³ and R⁴ is independently hydrogen or —OR^(c), where R^(c)is a non-ring forming hydroxy protecting group, or R³ and R⁴ togetherwith the carbon atoms to which they are attached to form an optionallysubstituted heterocyclyl, provided at least one of R¹ and R² togetherwith the carbon atoms to which they are attached to or R³ and R⁴together with the carbon atoms to which they are attached to form anoptionally substituted nitrogen atom containing heterocyclyl.
 31. Themethod of claim 30, wherein the olefin comprises a chiral or apro-chiral center.
 32. The method of claim 31, wherein the ketone isenantiomerically enriched chiral ketone.
 33. The method of claim 32,wherein the epoxide is enatiomerically enriched.
 34. The method of claim33, wherein the olefin is a cis-olefin or a terminal olefin.
 35. Themethod of claim 33, wherein the chiral ketone is selected from acompound of the formula:

and a stereoisomer thereof, wherein R⁷ is selected from the groupconsisting of hydrogen, alkyl, aryl, —(R⁸)_(n)—C(═O)—R⁹, and othernitrogen protecting group, where n is 0 or 1, R⁸ is alkylene, and R⁹ ishydroxy, alkyl, alkoxy, aryl, aryloxy and —NR^(a)R^(b), where R^(a) andR^(b) is independently hydrogen or alkyl; and each of R¹⁰ and R¹¹ isindependently selected from the group consisting of hydrogen, alkyl,aralkyl and aryl.
 36. The method of claim 30, wherein said oxidizingagent is selected from the group consisting of peracids, hydrogenperoxide, sodium hypochlorite, potassium peroxomonosulfate, sodiumperborate and hypofluoride (HOF).
 37. The method of claim 36, whereinsaid oxidizing agent is potassium peroxomonosulfate.
 38. The method ofclaim 30, wherein said admixture further comprises a base.
 39. Themethod of claim 30 further comprising maintaining pH of the admixture atfrom about pH 5 to about pH
 14. 40. The method of claim 30, wherein saidasymmetric epoxide is produced in an enantiomeric excess of at leastabout 80% ee.
 41. A method for stereoselectively epoxidizing acis-olefin or a terminal olefin comprising the steps of admixing achiral ketone, the cis- or the terminal olefin, and an oxidizing agentunder conditions sufficient to produce an asymmetric epoxide in at leastabout 80% ee.
 42. The method of claim 41, wherein said chiral ketone isof the formula:

wherein R⁷ is selected from the group consisting of hydrogen, alkyl,aryl, —(R⁸)_(n)—C(═O)R⁹, and other nitrogen protecting group, where n is0 or 1, R⁸ is alkylene, and R⁹ is hydroxy, alkyl, alkoxy, aryl, aryloxyand —NR^(a)R^(b), where R^(a) and R^(b) is independently hydrogen oralkyl; each of R¹⁰ and R¹¹ is independently selected from the groupconsisting of hydrogen, alkyl, aralkyl and aryl.
 43. The method of claim41, wherein said chiral ketone is of the formula:

and a stereoisomer thereof, wherein each of R⁵ and R⁶ is independentlyselected from the group consisting of hydrogen, and alkyl; and R⁷ isselected from the group consisting of hydrogen, alkyl, aryl,—(R⁸)_(n)—C(═O)R⁹, and other nitrogen protecting group, where n is 0 or1, R⁸ is alkylene, and R⁹ is hydroxy, alkyl, alkoxy, aryl, aryloxy and—NR^(a)R^(b), where R^(a) and R^(b) is independently hydrogen or alkyl.